WO2012088067A1

WO2012088067A1 - Methods for predicting and/or determining responsiveness to a histone deacetylase (hdac) inhibitor

Info

Publication number: WO2012088067A1
Application number: PCT/US2011/066085
Authority: WO
Inventors: Sarah S. Bacus
Original assignee: Quintiles Transnational Corp
Current assignee: Iqvia Inc
Priority date: 2010-12-20
Filing date: 2011-12-20
Publication date: 2012-06-28
Anticipated expiration: 2013-06-20

Abstract

The present disclosure provides methods for predicting the sensitivity (e.g., responsiveness) of a cell and/or biological sample obtained from a subject to treatment with a histone deacetylase (HDAC) inhibitor. Such methods may comprise detecting the expression of one or more biomarkers including, one or more miRNAs (e.g., one or more of miR-17, miR-20a, miR18a, miR19a, miR-19b or miR92a) and/or c-myc and/or the presence of a c-myc amplification (e.g., 3, 4, 5, 6,7, 8, 9 or 10 copies of c-myc per cell), in the cell and/or biological sample.

Description

TITLE

METHODS FOR PREDICTI NG AND/OR DETERMI NI NG RESPONSIVENESS TO

A HISTONE DEACETYLASE (HDAC) I NHI BITOR

FI ELD

[0001 ] The present disclosure provides methods for predicting the sensitivity (e.g., responsiveness) of a cell and/or biological sample obtained from a subject to treatment with a histone deacetylase (HDAC) inhibitor and methods for determining if a subject is responding to treatment with an HDAC inhibitor.

SEQUENCE LISTI NG

[0002] This disclosure includes a sequence listing submitted as a text file pursuant to 37 C.F.R. § 1 .52(e)(v) named CI-#9261548-v1 -3714714_92_ST25.TXT, created on December 16, 201 1 , with a size of 6,467 bytes, which is incorporated herein by reference. The attached sequence descriptions and Sequence Listing comply with the rules governing nucleotide and/or amino acid sequence disclosures in patent applications as set forth in 37 C.F.R. §§ 1 .821 -1 .825. The Sequence Listing contains the one letter code for nucleotide sequence characters and the three letter codes for amino acids as defined in conformity with the lUPAC-I UBMB standards described in Nucleic Acids Res. 13:3021 -3030 (1985) and in the Biochemical J. 219 (No. 2):345-373 (1984). The symbols and format used for nucleotide and amino acid sequence data comply with the rules set forth in 37 C.F.R. §1 .822.

BACKGROUND

[0003] The regulation of chromatin structure has emerged as a central mechanism for the control of gene expression. As a general paradigm, acetylation of the e-amino groups of lysine residues in the amino-terminal tails of nucleosomal histones is associated with transcriptional activation, while deacetylation is associated condensation of chromatin and transcriptional repression. Acetylation and deacetylation of histones is controlled by the enzymatic activity of histone acetyltransferases (HATs) and histone deacetylases (HDACs). Mammalian HDACs have been ordered into three classes based upon their similarity to known yeast factors. Class I H DACs (H DACs 1 , 2, 3 and 8) bear similarity to the yeast RPD3 protein, are located in the nucleus and are found in complexes associated with transcriptional co-repressors. Class I I HDACs (HDACs 4, 5, 6, 7 and 9) are similar to the yeast HDA1 protein, and have both nuclear and cytoplasmic subcellular localization. Class III HDACs form a structurally distant class of NAD dependent enzymes that are related to the yeast SIR2 proteins.

[0004] Recently, HDAC inhibitors have emerged as novel agents for multiple human diseases, including cancer, neurodegenerative diseases, psychiatric disorders, inflammation, autoimmune diseases and metabolic diseases. Compounds that are shown to inhibit HDAC activity fall into five structurally diverse classes: (1 ) hydroxamic acids; (2) cyclic tetrapeptides; (3) aliphatic acids; (4) benzamides; and (5) electrophilic ketones. Phenotypic changes induced by HDAC inhibitors (HDACi) include G1 , and G2/M cell cycle arrest, induction of apoptosis in tumor cells, inhibition of angiogenesis, immune modulation and promotion of cellular differentiation. HDACIs also modulate gene expression within tumor cells, including tumor suppressor genes. Anti-tumor activity has been demonstrated in vivo in animal models with a number of HDAC inhibitors.

SUMMARY

[0005] The present disclosure provides methods for predicting the sensitivity (e.g., responsiveness) of a cell and/or biological sample obtained from a subject (e.g., a human patient) to treatment with a histone deacetylase (HDAC) inhibitor and methods for determining if a subject is responding to treatment with a HDAC inhibitor. Such methods may comprise detecting the presence (e.g., expression) of one or more biomarkers including, one or more miRNAs (e.g., one or more of MiR-17, MiR-18A, Mir18B, Mir19A, Mir19B1 , Mir19B2, Mir20A, Mir92A1 , Mir92A2, Mir106A or Mir20B) and/or c-myc expression and/or a c-myc amplification (e.g., 3, 4, 5, 6 ,7, 8, 9 or 10 copies of c-myc per cell), in the cell and/or biological sample. The methods may be used to predict or determine the responsiveness of a subject to treatment with a HDAC inhibitor.

[0006] The present disclosure provides methods for predicting sensitivity of a test cell to a histone deacetylase (HDAC) inhibitor by obtaining a test cell; assaying the test cell for expression of one or more miRNAs; determining if expression of the one or more miRNAs in the test cell is elevated or reduced compared to a control cell or above or below a threshold; and employing the determination of the expression of the one or more miRNAs in the test cell to predict sensitivity of the test cell to the HDAC inhibitor.

[0007] In some embodiments of each or any of the above-mentioned or below- mentioned embodiments, the miRNA is one or more of miR-17, miR-20a, miR18a, miR19a, miR-19b or miR92a.

[0008] In some embodiments of each or any of the above-mentioned or below- mentioned embodiments, the miRNA is miRNA 17-92. [0009] In some embodiments of each or any of the above-mentioned or below- mentioned embodiments, the test cell is from a tumor.

[0010] In some embodiments of each or any of the above-mentioned or below- mentioned embodiments, the tumor is a breast or colon tumor.

[001 1 ] In some embodiments of each or any of the above-mentioned or below- mentioned embodiments, the test cell is from an aspirate, blood or serum.

[0012] In some embodiments of each or any of the above-mentioned or below- mentioned embodiments, the test cell is from a cancer patient.

[0013] In some embodiments of each or any of the above-mentioned or below- mentioned embodiments, the test cell is predicted to be sensitive to the HDAC inhibitor where expression of the one or more miRNAs in the test cell is elevated as compared to expression of the one or more miRNAs in the control cell or is above the threshold.

[0014] In some embodiments of each or any of the above-mentioned or below- mentioned embodiments, the test cell is predicted to not be sensitive to the HDAC inhibitor where expression of the one or more miRNAs in the test cell is reduced as compared to expression of the one or more miRNAs in the control cell or is less than the threshold.

[0015] In some embodiments of each or any of the above-mentioned or below- mentioned embodiments, the step of assaying the test cell for expression of one or more miRNAs is performed by in situ hybridization (ISH), Northern blot, qRT-PCR or microarray analysis.

[0016] In some embodiments of each or any of the above-mentioned or below- mentioned embodiments, the threshold is set at a level of miRNA expression above which a cell is known to be sensitive to treatment with the HDAC inhibitor and below which a cell is known to not be sensitive to treatment with the HDAC inhibitor.

[0017] In some embodiments of each or any of the above-mentioned or below- mentioned embodiments, the threshold is set at a level of miRNA expression below which a cell is known to be sensitive to treatment with the HDAC inhibitor and above which a cell is known to not be sensitive to treatment with the HDAC inhibitor.

[0018] In some embodiments of each or any of the above-mentioned or below- mentioned embodiments, the threshold is set at a level of miRNA expression above which 50%, 60%, 70%, 80%, 90%, 95%, or greater of cells respond to treatment with the HDAC inhibitor.

[0019] In some embodiments of each or any of the above-mentioned or below- mentioned embodiments, the threshold is set at a level of miRNA expression above which 50%, 60%, 70%, 80%, 90%, 95%, or greater of cells do not respond to treatment with the HDAC inhibitor. [0020] In some embodiments of each or any of the above-mentioned or below- mentioned embodiments, the threshold is set at a level of miRNA expression below which 50%, 60%, 70%, 80%, 90%, 95%, or greater of cells do not respond to treatment with the HDAC inhibitor.

[0021 ] In some embodiments of each or any of the above-mentioned or below- mentioned embodiments, the threshold is set at a level of miRNA expression below which 50%, 60%, 70%, 80%, 90%, 95%, or greater of cells respond to treatment with the HDAC inhibitor.

[0022] In some embodiments of each or any of the above-mentioned or below- mentioned embodiments, the control cell is the same cell type as the test cell.

[0023] In some embodiments of each or any of the above-mentioned or below- mentioned embodiments, the control cell is a different cell type than the test cell.

[0024] The present disclosure also provides methods for predicting responsiveness of a subject with a disease or disorder to a histone deacetylase (HDAC) inhibitor by obtaining a biological sample from the subject; assaying the biological sample for expression of one or more miRNAs; determining if expression of the one or more miRNAs in the biological sample is elevated or reduced compared to a control sample or above or below a threshold; and employing the determination of the expression of the one or more miRNAs in the biological sample to predict responsiveness of the subject to the HDAC inhibitor.

[0025] In some embodiments of each or any of the above-mentioned or below- mentioned embodiments, the miRNA is one or more of miR-17, miR-20a, miR18a, miR19a, miR-19b or miR92a.

[0026] In some embodiments of each or any of the above-mentioned or below- mentioned embodiments, the miRNA is miRNA 17-92.

[0027] In some embodiments of each or any of the above-mentioned or below- mentioned embodiments, the HDAC inhibitor is a small molecule.

[0028] In some embodiments of each or any of the above-mentioned or below- mentioned embodiments, the biological sample is from a tumor.

[0029] In some embodiments of each or any of the above-mentioned or below- mentioned embodiments, the tumor is a breast or colon tumor.

[0030] In some embodiments of each or any of the above-mentioned or below- mentioned embodiments, the biological sample is from an aspirate.

[0031 ] In some embodiments of each or any of the above-mentioned or below- mentioned embodiments, the biological sample is from a cancer patient.

[0032] In some embodiments of each or any of the above-mentioned or below- mentioned embodiments, the subject is predicted to be responsive to the HDAC inhibitor where expression of the one or more miRNAs in the biological sample is elevated as compared to the control sample or is greater than the threshold.

[0033] In some embodiments of each or any of the above-mentioned or below- mentioned embodiments, the subject is predicted to not be responsive to the HDAC inhibitor where expression of the one or more miRNAs in the biological sample is reduced as compared to the control sample or is less than the threshold.

[0034] In some embodiments of each or any of the above-mentioned or below- mentioned embodiments, the step of assaying the biological sample for expression of one or more miRNAs is performed by in situ hybridization (ISH), Northern blot or microarray analysis.

[0035] In some embodiments of each or any of the above-mentioned or below- mentioned embodiments, the threshold is set at a level of miRNA expression above which a subject is known to respond to treatment with the HDAC inhibitor and below which a subject is known to not respond to treatment with the HDAC inhibitor.

[0036] In some embodiments of each or any of the above-mentioned or below- mentioned embodiments, the threshold is set at a level of miRNA expression below which a subject is known to respond to treatment with the HDAC inhibitor and above which a subject is known to not respond to treatment with the HDAC inhibitor.

[0037] In some embodiments of each or any of the above-mentioned or below- mentioned embodiments, the threshold is set at a level of miRNA expression above which 50%, 60%, 70%, 80%, 90%, or 95% of subject(s) respond to treatment with the HDAC inhibitor.

[0038] In some embodiments of each or any of the above-mentioned or below- mentioned embodiments, the threshold is set at a level of miRNA expression above which 50%, 60%, 70%, 80%, 90%, 95% or greater of subject(s) do not respond to treatment with the HDAC inhibitor.

[0039] In some embodiments of each or any of the above-mentioned or below- mentioned embodiments, the threshold is set at a level of miRNA expression below which 50%, 60%, 70%, 80%, 90%, 95%, or greater of subject(s) respond to treatment with the HDAC inhibitor.

[0040] In some embodiments of each or any of the above-mentioned or below- mentioned embodiments, the threshold is set at a level of miRNA expression below which 50%, 60%, 70%, 80%, 90%, 95%, or greater of subject(s) do not respond to treatment with the HDAC inhibitor.

[0041 ] In some embodiments of each or any of the above-mentioned or below- mentioned embodiments, the disease or disorder is cancer. [0042] In some embodiments of each or any of the above-mentioned or below- mentioned embodiments, the cancer is selected from the group consisting of gastrointestinal, prostate cancer, ovarian cancer, breast cancer, head and neck cancer, lung cancer, non-small cell lung cancer, cancer of the nervous system, kidney cancer, retina cancer, skin cancer, liver cancer, pancreatic cancer, genital-urinary cancer and bladder cancer.

[0043] In some embodiments of each or any of the above-mentioned or below- mentioned embodiments, the subject is a cancer patient.

[0044] The present disclosure also provides methods for treating a subject with a disease or disorder by obtaining a biological sample from a subject, assaying the biological sample for expression of one or more miRNAs, determining if expression of the one or more miRNAs in the biological sample is elevated or reduced compared to a control sample or above or below a threshold, employing the determination of the expression of the one or more miRNAs in the biological sample to predict responsiveness of the subject to the HDAC inhibitor, and administering to the subject a therapeutically effective amount of one or more histone deacetylase (HDAC) inhibitors where the subject is predicted to be responsive to the HDAC inhibitor.

[0045] In some embodiments of each or any of the above-mentioned or below- mentioned embodiments, the miRNA is one or more of miR-17, miR-20a, miR18a, miR19a, miR-19b or miR92a.

[0046] In some embodiments of each or any of the above-mentioned or below- mentioned embodiments, the miRNA is miRNA 17-92.

[0047] In some embodiments of each or any of the above-mentioned or below- mentioned embodiments, the HDAC inhibitor is a small molecule.

[0048] In some embodiments of each or any of the above-mentioned or below- mentioned embodiments, the biological sample is from a tumor.

[0049] In some embodiments of each or any of the above-mentioned or below- mentioned embodiments, the tumor is a breast or colon tumor.

[0050] In some embodiments of each or any of the above-mentioned or below- mentioned embodiments, the biological sample is from an aspirate.

[0051 ] In some embodiments of each or any of the above-mentioned or below- mentioned embodiments, the biological sample is from a cancer patient.

[0052] In some embodiments of each or any of the above-mentioned or below- mentioned embodiments, the subject is predicted to be responsive to the HDAC inhibitor where expression of the one or more miRNAs in the biological sample is elevated as compared to the control sample or is greater than the threshold. [0053] In some embodiments of each or any of the above-mentioned or below- mentioned embodiments, the subject is predicted to not be responsive to the HDAC inhibitor where expression of the one or more miRNAs in the biological sample is reduced as compared to the control sample or is less than the threshold.

[0054] In some embodiments of each or any of the above-mentioned or below- mentioned embodiments, the disease or disorder is cancer.

[0055] In some embodiments of each or any of the above-mentioned or below- mentioned embodiments, the cancer is selected from the group consisting of gastrointestinal cancer, prostate cancer, ovarian cancer, breast cancer, head and neck cancer, lung cancer, non-small cell lung cancer, cancer of the nervous system, kidney cancer, retina cancer, skin cancer, liver cancer, pancreatic cancer, genital-urinary cancer and bladder cancer.

[0056] In some embodiments of each or any of the above-mentioned or below- mentioned embodiments, the step of assaying the biological sample for expression of one or more miRNAs is performed by in situ hybridization (ISH), Northern blot or microarray analysis.

[0057] In some embodiments of each or any of the above-mentioned or below- mentioned embodiments, the threshold is set at a level of miRNA expression above which a subject is known to respond to treatment with the HDAC inhibitor and below which a subject is known to not respond to treatment with the HDAC inhibitor.

[0058] In some embodiments of each or any of the above-mentioned or below- mentioned embodiments, the threshold is set at a level of miRNA below which a subject is known to respond to treatment with the HDAC inhibitor and above which a subject is known to not respond to treatment with the HDAC inhibitor.

[0059] In some embodiments of each or any of the above-mentioned or below- mentioned embodiments, the threshold is set at a level of miRNA expression above which 50%, 60%, 70%, 80%, 90%, 95%, or greater of subject(s) respond to treatment with the HDAC inhibitor.

[0060] In some embodiments of each or any of the above-mentioned or below- mentioned embodiments, the threshold is set at a level of miRNA expression above which 50%, 60%, 70%, 80%, 90%, 95% or greater of subject(s) do not respond to treatment with the HDAC inhibitor.

[0061 ] In some embodiments of each or any of the above-mentioned or below- mentioned embodiments, the threshold is set at a level of miRNA expression below which 50%, 60%, 70%, 80%, 90%, 95%, or greater of subject(s) respond to treatment with the HDAC inhibitor. [0062] In some embodiments of each or any of the above-mentioned or below- mentioned embodiments, the threshold is set at a level of miRNA expression below which 50%, 60%, 70%, 80%, 90%, 95%, or greater of subject(s) do not respond to treatment with the HDAC inhibitor.

[0063] In some embodiments of each or any of the above-mentioned or below- mentioned embodiments, the subject is a cancer patient.

[0064] In some embodiments of each or any of the above-mentioned or below- mentioned embodiments, the therapeutically effective amount of one or more HDAC inhibitors are optionally adapted for a co-treatment with radiotherapy or radio- immunotherapy.

[0065] The present disclosure also provides methods for selecting subjects for a clinical trial that are responsive to a histone deacetylase (HDAC) inhibitor by obtaining a biological sample from the subjects assaying the biological samples obtained from the subjects for expression of one or more miRNAs determining if expression of the one or more miRNAs in the biological sample is elevated or reduced compared to a control sample or above or below a threshold employing the determination of the expression of the one or more miRNAs in the biological sample to predict responsiveness of the subject to the HDAC inhibitor, and selecting subjects for inclusion in a clinical trial that are responsive to the HDAC inhibitor.

[0066] In some embodiments of each or any of the above-mentioned or below- mentioned embodiments, the miRNA is one or more of miR-17, miR-20a, miR18a, miR19a, miR-19b or miR92a.

[0067] In some embodiments of each or any of the above-mentioned or below- mentioned embodiments, the miRNA is miRNA 17-92.

[0068] In some embodiments of each or any of the above-mentioned or below- mentioned embodiments, the HDAC inhibitor is a small molecule.

[0069] In some embodiments of each or any of the above-mentioned or below- mentioned embodiments, the biological sample is from a tumor.

[0070] In some embodiments of each or any of the above-mentioned or below- mentioned embodiments, the tumor is a breast or colon tumor.

[0071 ] In some embodiments of each or any of the above-mentioned or below- mentioned embodiments, the biological sample is from an aspirate.

[0072] In some embodiments of each or any of the above-mentioned or below- mentioned embodiments, the biological sample is from a cancer patient.

[0073] In some embodiments of each or any of the above-mentioned or below- mentioned embodiments, the subject is predicted to be responsive to the HDAC inhibitor where expression of the one or more miRNAs in the biological sample is elevated as compared to the control sample or is greater than the threshold.

[0074] In some embodiments of each or any of the above-mentioned or below- mentioned embodiments, the subject is predicted to not be responsive to the HDAC inhibitor where expression of the one or more miRNAs in the biological sample is reduced as compared to the control sample or is less than the threshold.

[0075] In some embodiments of each or any of the above-mentioned or below- mentioned embodiments, the disease or disorder is cancer.

[0076] In some embodiments of each or any of the above-mentioned or below- mentioned embodiments, the cancer is selected from the group consisting of gastrointestinal cancer, prostate cancer, ovarian cancer, breast cancer, head and neck cancer, lung cancer, non-small cell lung cancer, cancer of the nervous system, kidney cancer, retina cancer, skin cancer, liver cancer, pancreatic cancer, genital-urinary cancer and bladder cancer.

[0077] In some embodiments of each or any of the above-mentioned or below- mentioned embodiments, the step of assaying the test cell for expression of one or more miRNAs is performed by in situ hybridization (ISH), Northern blot or microarray analysis.

[0078] In some embodiments of each or any of the above-mentioned or below- mentioned embodiments, the threshold is set at a level of miRNA expression above which a subject is known to respond to treatment with the HDAC inhibitor and below which a subject is known to not respond to treatment with the HDAC inhibitor.

[0079] In some embodiments of each or any of the above-mentioned or below- mentioned embodiments, wherein the threshold is set at a level of miRNA expression below which a subject is known to respond to treatment with the HDAC inhibitor and above which a subject is known to not respond to treatment with the HDAC inhibitor.

[0080] In some embodiments of each or any of the above-mentioned or below- mentioned embodiments, the threshold is set at a level of miRNA expression above which 50%, 60%, 70%, 80%, 90%, 95%, or greater of subject(s) respond to treatment with the HDAC inhibitor.

[0081 ] In some embodiments of each or any of the above-mentioned or below- mentioned embodiments, the threshold is set at a level of miRNA expression above which 50%, 60%, 70%, 80%, 90%, 95% or greater of subject(s) do not respond to treatment with the HDAC inhibitor.

[0082] In some embodiments of each or any of the above-mentioned or below- mentioned embodiments, the threshold is set at a level of miRNA expression below which 50%, 60%, 70%, 80%, 90%, 95%, or greater of subject(s) respond to treatment with the HDAC inhibitor. [0083] In some embodiments of each or any of the above-mentioned or below- mentioned embodiments, the threshold is set at a level of miRNA expression below which 50%, 60%, 70%, 80%, 90%, 95%, or greater of subject(s) do not respond to treatment with the HDAC inhibitor.

[0084] In some embodiments of each or any of the above-mentioned or below- mentioned embodiments, the subject is a cancer patient.

[0085] In some embodiments of each or any of the above-mentioned or below- mentioned embodiments, the method further includes seeking regulatory approval for the histone deacetylase (HDAC) inhibitor.

[0086] In some embodiments of each or any of the above-mentioned or below- mentioned embodiments, the clinical trial is a phase I, phase II, phase III or phase IV clinical trial.

[0087] The present disclosure also provides methods for screening a test cell for sensitivity to a histone deacetylase (HDAC) inhibitor, the method by obtaining a test cell assaying the test cell for expression of one or more miRNAs, and determining if expression of the one or more miRNAs in the test cell is elevated or reduced compared to a control cell or above or below a threshold, wherein the test cell is determined to be sensitive to the HDAC inhibitor where expression of the one or more miRNAs in the test cell is elevated as compared to expression of the one or more miRNAs in the control cell or is above the threshold and wherein the test cell is determined to not be sensitive to the HDAC inhibitor where expression of the one or more miRNAs in the test cell is reduced as compared to expression of the one or more miRNAs in the control cell or is less than the threshold.

[0088] In some embodiments of each or any of the above-mentioned or below- mentioned embodiments, the miRNA is one or more of miR-17, miR-20a, miR18a, miR19a, miR-19b or miR92a.

[0089] In some embodiments of each or any of the above-mentioned or below- mentioned embodiments, the miRNA is miRNA 17-92.

[0090] In some embodiments of each or any of the above-mentioned or below- mentioned embodiments, the HDAC inhibitor is a small molecule.

[0091 ] In some embodiments of each or any of the above-mentioned or below- mentioned embodiments, the test cell is from a tumor.

[0092] In some embodiments of each or any of the above-mentioned or below- mentioned embodiments, the tumor is a breast or colon tumor.

[0093] In some embodiments of each or any of the above-mentioned or below- mentioned embodiments, the test cell is from an aspirate. [0094] In some embodiments of each or any of the above-mentioned or below- mentioned embodiments, the test cell is from a cancer patient.

[0095] In some embodiments of each or any of the above-mentioned or below- mentioned embodiments, the step of assaying the test cell for expression of one or more miRNAs is performed by in situ hybridization (ISH), Northern blot or microarray analysis.

[0096] In some embodiments of each or any of the above-mentioned or below- mentioned embodiments, the threshold is set at a level of miRNA expression above which a cell is known to be sensitive to treatment with the HDAC inhibitor and below which a cell is known to not be sensitive to treatment with the HDAC inhibitor.

[0097] In some embodiments of each or any of the above-mentioned or below- mentioned embodiments, the threshold is set at a level of miRNA expression below which a cell is known to be sensitive to treatment with the HDAC inhibitor and above which a cell is known to not be sensitive to treatment with the HDAC inhibitor.

[0098] In some embodiments of each or any of the above-mentioned or below- mentioned embodiments, the threshold is set at a level of miRNA expression above which 50%, 60%, 70%, 80%, 90%, 95%, or greater of cells respond to treatment with the HDAC inhibitor.

[0099] In some embodiments of each or any of the above-mentioned or below- mentioned embodiments, the threshold is set at a level of miRNA expression above which 50%, 60%, 70%, 80%, 90%, 95%, or greater of cells do not respond to treatment with the HDAC inhibitor.

[00100] In some embodiments of each or any of the above-mentioned or below- mentioned embodiments, the threshold is set at a level of miRNA expression below which 50%, 60%, 70%, 80%, 90%, 95%, or greater of cells do not respond to treatment with the HDAC inhibitor.

[00101] In some embodiments of each or any of the above-mentioned or below- mentioned embodiments, the threshold is set at a level of miRNA expression below which 50%, 60%, 70%, 80%, 90%, 95%, or greater of cells respond to treatment with the HDAC inhibitor.

[00102] In some embodiments of each or any of the above-mentioned or below- mentioned embodiments, the control cell is the same cell type as the test cell.

[00103] In some embodiments of each or any of the above-mentioned or below- mentioned embodiments, the control cell is a different cell type than the test cell.

[00104] The present disclosure also provides methods for predicting sensitivity of a test cell to a histone deacetylase (HDAC) inhibitor by obtaining a test cell, assaying the test cell for c-myc amplification, determining if c-myc expression and/or c-myc amplification in the test cell in increased or decreased as compared to a control cell or above or below a threshold, and employing the determination of c-myc expression and/or c-myc amplification in the test cell to predict sensitivity of the test cell to the HDAC inhibitor.

[00105] In some embodiments of each or any of the above-mentioned or below- mentioned embodiments, the HDAC inhibitor is a small molecule.

[00106] In some embodiments of each or any of the above-mentioned or below- mentioned embodiments, the test cell is from a tumor.

[00107] In some embodiments of each or any of the above-mentioned or below- mentioned embodiments, the tumor is a breast or colon tumor.

[00108] In some embodiments of each or any of the above-mentioned or below- mentioned embodiments, the test cell is from an aspirate.

[00109] In some embodiments of each or any of the above-mentioned or below- mentioned embodiments, the test cell is from a cancer patient.

[001 10] In some embodiments of each or any of the above-mentioned or below- mentioned embodiments, the test cell is predicted to be sensitive to the HDAC inhibitor where c-myc expression and/or c-myc amplification is greater in the test cell as compared to the control cell or is above the threshold.

[001 1 1] In some embodiments of each or any of the above-mentioned or below- mentioned embodiments, the test cell is predicted to not be sensitive to the HDAC inhibitor where c-myc expression and/or c-myc amplification is reduced in the test cell as compared to the control cell or is less than the threshold.

[001 12] In some embodiments of each or any of the above-mentioned or below- mentioned embodiments, the step of assaying the test cell for c-myc expression and/or c- myc amplification is performed by in situ hybridization (ISH), Northern blot or microarray analysis.

[001 13] In some embodiments of each or any of the above-mentioned or below- mentioned embodiments, the threshold is set at a level of c-myc expression and/or c-myc amplification above which a cell is known to be sensitive to treatment with the HDAC inhibitor and below which a cell is known to not be sensitive to treatment with the HDAC inhibitor.

[001 14] In some embodiments of each or any of the above-mentioned or below- mentioned embodiments, the threshold is set at a level of c-myc expression and/or c-myc amplification below which a cell is known to be sensitive to treatment with the HDAC inhibitor and above which a cell is known to not be sensitive to treatment with the HDAC inhibitor.

[001 15] In some embodiments of each or any of the above-mentioned or below- mentioned embodiments, the threshold is set at a level of c-myc expression and/or c-myc amplification above which 50%, 60%, 70%, 80%, 90%, or 95% of cells respond to treatment with a HDAC.

[001 16] In some embodiments of each or any of the above-mentioned or below- mentioned embodiments, the threshold is set at a level of c-myc expression and/or c-myc amplification above which 50%, 60%, 70%, 80%, 90%, or 95% of cells do not respond to treatment with a HDAC.

[001 17] In some embodiments of each or any of the above-mentioned or below- mentioned embodiments, the threshold is set at a level of c-myc expression and/or c-myc amplification below which 50%, 60%, 70%, 80%, 90%, or 95% of cells respond to treatment with a HDAC inhibitor.

[001 18] In some embodiments of each or any of the above-mentioned or below- mentioned embodiments, the threshold is set at a level of c-myc expression and/or c-myc amplification below which 50%, 60%, 70%, 80%, 90%, or 95% of cells do not respond to treatment with a HDAC inhibitor.

[001 19] In some embodiments of each or any of the above-mentioned or below- mentioned embodiments, the control cell is the same cell type as the test cell.

[00120] In some embodiments of each or any of the above-mentioned or below- mentioned embodiments, the control cell is a different cell type than the test cell.

[00121] The present disclosure also provides methods fori 17. A method for predicting responsiveness of a subject with a disease or disorder to a histone deacetylase (HDAC) inhibitor by obtaining a biological sample from the subject, assaying the biological sample for c-myc expression and/or c-myc amplification, determining if c-myc expression and/or c-myc amplification in the biological sample is increased or decreased as compared to a control sample or above or below a threshold, and employing the determination of c-myc expression and/or c-myc amplification in the biological sample to predict responsiveness of the subject to the HDAC inhibitor.

[00122] In some embodiments of each or any of the above-mentioned or below- mentioned embodiments, the HDAC inhibitor is a small molecule.

[00123] In some embodiments of each or any of the above-mentioned or below- mentioned embodiments, the biological sample is from a tumor.

[00124] In some embodiments of each or any of the above-mentioned or below- mentioned embodiments, the tumor is a breast or colon tumor.

[00125] In some embodiments of each or any of the above-mentioned or below- mentioned embodiments, the biological sample is from an aspirate.

[00126] In some embodiments of each or any of the above-mentioned or below- mentioned embodiments, the biological sample is from a cancer patient. [00127] In some embodiments of each or any of the above-mentioned or below- mentioned embodiments, the subject is predicted to be responsive to the HDAC inhibitor where c-myc expression and/or c-myc amplification is elevated in the biological sample as compared to the control sample or is greater than the threshold.

[00128] In some embodiments of each or any of the above-mentioned or below- mentioned embodiments, the subject is predicted to not be responsive to the HDAC inhibitor where c-myc expression and/or c-myc amplification is reduced in the biological sample as compared to the control sample or is less than the threshold.

[00129] In some embodiments of each or any of the above-mentioned or below- mentioned embodiments, the step of assaying the biological sample for c-myc expression and/or c-myc amplification is performed by in situ hybridization (ISH), Northern blot or microarray analysis.

[00130] In some embodiments of each or any of the above-mentioned or below- mentioned embodiments, the threshold is set at a level of c-myc expression and/or c-myc amplification above which a subject is known to respond to treatment with the HDAC inhibitor and below which a subject is known to not respond to treatment with the HDAC inhibitor.

[00131] In some embodiments of each or any of the above-mentioned or below- mentioned embodiments, the threshold is set at a level of c-myc expression and/or c-myc amplification below which a subject is known to respond to treatment with the HDAC inhibitor and above which a subject is known to not respond to treatment with the HDAC inhibitor.

[00132] In some embodiments of each or any of the above-mentioned or below- mentioned embodiments, the threshold is set at a level of c-myc expression and/or c-myc amplification above which 50%, 60%, 70%, 80%, 90%, or 95% of subject(s) respond to treatment with the HDAC inhibitor.

[00133] In some embodiments of each or any of the above-mentioned or below- mentioned embodiments, the threshold is set at a level of c-myc expression and/or c-myc amplification above which 50%, 60%, 70%, 80%, 90%, or 95% of subject(s) do not respond to treatment with the HDAC inhibitor.

[00134] In some embodiments of each or any of the above-mentioned or below- mentioned embodiments, the threshold is set at a level of c-myc expression and/or c-myc amplification below which 50%, 60%, 70%, 80%, 90%, or 95% of subject(s) respond to treatment with the HDAC inhibitor.

[00135] In some embodiments of each or any of the above-mentioned or below- mentioned embodiments, the threshold is set at a level of c-myc expression and/or c-myc amplification below which 50%, 60%, 70%, 80%, 90%, or 95% of subject(s) do not respond to treatment with the HDAC inhibitor.

[00136] In some embodiments of each or any of the above-mentioned or below- mentioned embodiments, the disease or disorder is cancer.

[00137] In some embodiments of each or any of the above-mentioned or below- mentioned embodiments, the cancer is selected from the group consisting of gastrointestinal, prostate cancer, ovarian cancer, breast cancer, head and neck cancer, lung cancer, non-small cell lung cancer, cancer of the nervous system, kidney cancer, retina cancer, skin cancer, liver cancer, pancreatic cancer, genital-urinary cancer and bladder cancer.

[00138] In some embodiments of each or any of the above-mentioned or below- mentioned embodiments, the subject is a cancer patient.

[00139] The present disclosure also provides methods for treating a subject with a disease or disorder by obtaining a biological sample from a subject, assaying the biological sample for c-myc expression and/or c-myc amplification, determining if c-myc expression and/or c-myc amplification in the cell is elevated or reduced compared to a control sample or above or below a threshold, employing the determination of c-myc expression and/or c-myc amplification in the biological sample to predict responsiveness of the subject to the HDAC inhibitor, and administering to the subject a therapeutically effective amount of one or more histone deacetylase (HDAC) inhibitors where the subject is predicted to be responsive to the HDAC inhibitor.

[00140] In some embodiments of each or any of the above-mentioned or below- mentioned embodiments, the HDAC inhibitor is a small molecule.

[00141] In some embodiments of each or any of the above-mentioned or below- mentioned embodiments, the biological sample is from a tumor.

[00142] In some embodiments of each or any of the above-mentioned or below- mentioned embodiments, the tumor is a breast or colon tumor.

[00143] In some embodiments of each or any of the above-mentioned or below- mentioned embodiments, the biological sample is from an aspirate.

[00144] In some embodiments of each or any of the above-mentioned or below- mentioned embodiments, the biological sample is from a cancer patient.

[00145] In some embodiments of each or any of the above-mentioned or below- mentioned embodiments, the subject is predicted to be responsive to the HDAC inhibitor where c-myc expression and/or c-myc amplification is elevated in the biological sample as compared to the control sample or is greater than the threshold. [00146] In some embodiments of each or any of the above-mentioned or below- mentioned embodiments, the subject is predicted to not be responsive to the HDAC inhibitor where c-myc expression and/or c-myc amplification is reduced in the biological sample as compared to the control sample or is less than the threshold.

[00147] In some embodiments of each or any of the above-mentioned or below- mentioned embodiments, the disease or disorder is cancer.

[00148] In some embodiments of each or any of the above-mentioned or below- mentioned embodiments, the cancer is selected from the group consisting of gastrointestinal cancer, prostate cancer, ovarian cancer, breast cancer, head and neck cancer, lung cancer, non-small cell lung cancer, cancer of the nervous system, kidney cancer, retina cancer, skin cancer, liver cancer, pancreatic cancer, genital-urinary cancer and bladder cancer.

[00149] In some embodiments of each or any of the above-mentioned or below- mentioned embodiments, the step of assaying the test cell for c-myc expression and/or c- myc amplification is performed by in situ hybridization (ISH), Northern blot or microarray analysis.

[00150] In some embodiments of each or any of the above-mentioned or below- mentioned embodiments, the threshold is set at a level of c-myc expression and/or c-myc amplification above which a subject is known to respond to treatment with the HDAC inhibitor and below which a subject is known to not respond to treatment with the HDAC inhibitor.

[00151] In some embodiments of each or any of the above-mentioned or below- mentioned embodiments, the threshold is set at a level of c-myc expression and/or c-myc amplification below which a subject is known to respond to treatment with the HDAC inhibitor and above which a subject is known to not respond to treatment with the HDAC inhibitor.

[00152] In some embodiments of each or any of the above-mentioned or below- mentioned embodiments, the threshold is set at a level of c-myc expression and/or c-myc amplification above which 50%, 60%, 70%, 80%, 90%, or 95% of subject(s) respond to treatment with the HDAC inhibitor.

[00153] In some embodiments of each or any of the above-mentioned or below- mentioned embodiments, the threshold is set at a level of c-myc expression and/or c-myc amplification above which 50%, 60%, 70%, 80%, 90%, or 95% of subject(s) do not respond to treatment with the HDAC inhibitor.

[00154] In some embodiments of each or any of the above-mentioned or below- mentioned embodiments, the threshold is set at a level of c-myc expression and/or c-myc amplification below which 50%, 60%, 70%, 80%, 90%, or 95% of subject(s) respond to treatment with the HDAC inhibitor. [00155] In some embodiments of each or any of the above-mentioned or below- mentioned embodiments, the threshold is set at a level of c-myc expression and/or c-myc amplification below which 50%, 60%, 70%, 80%, 90%, or 95% of subject(s) do not respond to treatment with the HDAC inhibitor.

[00156] In some embodiments of each or any of the above-mentioned or below- mentioned embodiments, the subject is a cancer patient.

[00157] In some embodiments of each or any of the above-mentioned or below- mentioned embodiments, the therapeutically effective amount of one or more HDAC inhibitors are optionally adapted for a co-treatment with radiotherapy or radio- immunotherapy.

[00158] The present disclosure also provides methods for selecting subjects for a clinical trial that are responsive to a histone deacetylase (HDAC) inhibitor by obtaining a biological sample from the subjects, assaying the biological samples obtained from the subjects for c-myc expression and/or c-myc amplification, determining if c-myc expression and/or amplification in the biological sample is elevated or reduced compared to a control sample or above or below a threshold, employing the determination of the c-myc expression and/or amplification in the biological sample to predict responsiveness of the subject to the HDAC inhibitor, and selecting subjects for inclusion in a clinical trial that are responsive to the HDAC inhibitor.

[00159] In some embodiments of each or any of the above-mentioned or below- mentioned embodiments, the HDAC inhibitor is a small molecule.

[00160] In some embodiments of each or any of the above-mentioned or below- mentioned embodiments, the biological sample is from a tumor.

[00161] In some embodiments of each or any of the above-mentioned or below- mentioned embodiments, the tumor is a breast or colon tumor.

[00162] In some embodiments of each or any of the above-mentioned or below- mentioned embodiments, the biological sample is from an aspirate.

[00163] In some embodiments of each or any of the above-mentioned or below- mentioned embodiments, the biological sample is from a cancer patient.

[00164] In some embodiments of each or any of the above-mentioned or below- mentioned embodiments, the subject is predicted to be responsive to the HDAC inhibitor where c-myc expression and/or c-myc amplification is elevated in the biological sample as compared to the control sample or is greater than the threshold.

[00165] In some embodiments of each or any of the above-mentioned or below- mentioned embodiments, the subject is predicted to not be responsive to the HDAC inhibitor where c-myc expression and/or c-myc amplification is reduced in the biological sample as compared to the control sample or is less than the threshold.

[00166] In some embodiments of each or any of the above-mentioned or below- mentioned embodiments, the disease or disorder is cancer.

[00167] In some embodiments of each or any of the above-mentioned or below- mentioned embodiments, the cancer is selected from the group consisting of gastrointestinal cancer, prostate cancer, ovarian cancer, breast cancer, head and neck cancer, lung cancer, non-small cell lung cancer, cancer of the nervous system, kidney cancer, retina cancer, skin cancer, liver cancer, pancreatic cancer, genital-urinary cancer and bladder cancer.

[00168] In some embodiments of each or any of the above-mentioned or below- mentioned embodiments, the step of assaying the test cell for c-myc expression and/or amplification is performed by in situ hybridization (ISH), Northern blot or microarray analysis.

[00169] In some embodiments of each or any of the above-mentioned or below- mentioned embodiments, the threshold is set at a level of c-myc expression and/or c-myc amplification above which a subject is known to respond to treatment with the HDAC inhibitor and below which a subject is known to not respond to treatment with the HDAC inhibitor.

[00170] In some embodiments of each or any of the above-mentioned or below- mentioned embodiments, the threshold is set at a level of c-myc expression and/or c-myc amplification above which a subject is known to respond to treatment with the HDAC inhibitor and below which a subject is known to not respond to treatment with the HDAC inhibitor.

[00171] In some embodiments of each or any of the above-mentioned or below- mentioned embodiments, the threshold is set at a level of c-myc expression and/or c-myc amplification above which 50%, 60%, 70%, 80%, 90%, or 95% of subject(s) respond to treatment with the HDAC inhibitor.

[00172] In some embodiments of each or any of the above-mentioned or below- mentioned embodiments, the threshold is set at a level of c-myc expression and/or c-myc amplification above which 50%, 60%, 70%, 80%, 90%, or 95% of subject(s) do not respond to treatment with the HDAC inhibitor.

[00173] In some embodiments of each or any of the above-mentioned or below- mentioned embodiments, the threshold is set at a level of c-myc expression and/or c-myc amplification below which 50%, 60%, 70%, 80%, 90%, or 95% of subject(s) respond to treatment with the HDAC inhibitor.

[00174] In some embodiments of each or any of the above-mentioned or below- mentioned embodiments, the threshold is set at a level of c-myc expression and/or c-myc amplification below which 50%, 60%, 70%, 80%, 90%, or 95% of subject(s) do not respond to treatment with the HDAC inhibitor.

[00175] In some embodiments of each or any of the above-mentioned or below- mentioned embodiments, the subject is a cancer patient.

[00176] In some embodiments of each or any of the above-mentioned or below- mentioned embodiments, the method also includes seeking regulatory approval for the histone deacetylase (HDAC) inhibitor.

[00177] In some embodiments of each or any of the above-mentioned or below- mentioned embodiments, the clinical trial is a phase I, phase II, phase III or phase IV clinical trial.

[00178] The present disclosure also provides methods for screening a test cell for sensitivity to a histone deacetylase (HDAC) inhibitor by obtaining a test cell, assaying the test cell for c-myc expression and/or c-myc amplification; an, determining if c-myc expression and/or c-myc amplification in the test cell is elevated or reduced compared to a control cell or above or below a threshold, wherein the test cell is determined to be sensitive to the HDAC inhibitor where c-myc expression and/or c-myc amplification in the test cell is elevated as compared to c-myc expression and/or c-myc amplification in the control cell or is above the threshold and wherein the test cell is determined to not be sensitive to the HDAC inhibitor where c-myc expression and/or c-myc amplification in the test cell is reduced as compared to c-myc expression and/or c-myc amplification in the control cell or is less than the threshold.

[00179] In some embodiments of each or any of the above-mentioned or below- mentioned embodiments, the HDAC inhibitor is a small molecule.

[00180] In some embodiments of each or any of the above-mentioned or below- mentioned embodiments, the test cell is from a tumor.

[00181] In some embodiments of each or any of the above-mentioned or below- mentioned embodiments, the tumor is a breast or colon tumor.

[00182] In some embodiments of each or any of the above-mentioned or below- mentioned embodiments, the test cell is from an aspirate.

[00183] In some embodiments of each or any of the above-mentioned or below- mentioned embodiments, the test cell is from a cancer patient.

[00184] In some embodiments of each or any of the above-mentioned or below- mentioned embodiments, the step of assaying the test cell for c-myc expression and/or c- myc amplification is performed by in situ hybridization (ISH), Northern blot or microarray analysis. [00185] In some embodiments of each or any of the above-mentioned or below- mentioned embodiments, the threshold is set at a level of c-myc expression and/or c-myc amplification above which a cell is known to be sensitive to treatment with the HDAC inhibitor and below which a cell is known to not be sensitive to treatment with the HDAC inhibitor.

[00186] In some embodiments of each or any of the above-mentioned or below- mentioned embodiments, the threshold is set at a level of c-myc expression and/or c-myc amplification below which a cell is known to be sensitive to treatment with the HDAC inhibitor and above which a cell is known to not be sensitive to treatment with the HDAC inhibitor.

[00187] In some embodiments of each or any of the above-mentioned or below- mentioned embodiments, the threshold is set at a level of c-myc expression and/or c-myc amplification above which 50%, 60%, 70%, 80%, 90%, 95%, or greater of cells respond to treatment with a HDAC.

[00188] In some embodiments of each or any of the above-mentioned or below- mentioned embodiments, the threshold is set at a level of c-myc expression and/or c-myc amplification above which 50%, 60%, 70%, 80%, 90%, 95%, or greater of cells do not respond to treatment with a HDAC.

[00189] In some embodiments of each or any of the above-mentioned or below- mentioned embodiments, the threshold is set at a level of c-myc expression and/or c-myc amplification below which 50%, 60%, 70%, 80%, 90%, 95%, or greater of cells respond to treatment with a HDAC inhibitor.

[00190] In some embodiments of each or any of the above-mentioned or below- mentioned embodiments, the threshold is set at a level of c-myc expression and/or c-myc amplification below which 50%, 60%, 70%, 80%, 90%, 95%, or greater of cells do not respond to treatment with a HDAC inhibitor.

[00191] In some embodiments of each or any of the above-mentioned or below- mentioned embodiments, the control cell is the same cell type as the test cell.

[00192] In some embodiments of each or any of the above-mentioned or below- mentioned embodiments, the control cell is a different cell type than the test cell.

[00193] The present disclosure also provides methods for predicting responsiveness of a subject with a disease or disorder to a histone deacetylase (HDAC) inhibitor by obtaining a biological sample from the subject, assaying the biological sample for expression of one or more miRNAs and/or c-myc and/or a c-myc amplification, determining if expression of the one or more miRNAs in the cell is elevated or reduced compared to a control sample or above or below a threshold;, determining if expression of c-myc in the cell is elevated or reduced compared to a control sample or above or below a threshold, determining if c-myc is amplified in the biological sample as compared to a control sample or above or below a threshold, and employing the determination of the expression of the one or more miRNAs and/or c-myc and/or c-myc amplification in the biological sample to predict responsiveness of the subject to the HDAC inhibitor.

[00194] The present disclosure also provides methods for determining if a subject with a disease or disorder is responding to treatment with a histone deacetylase (HDAC) inhibitor by obtaining a biological sample from the subject, assaying the biological sample for expression of one or more miRNAs, determining if expression of the one or more miRNAs in the biological sample is elevated or reduced compared to a control sample or above or below a threshold, and employing the determination of the expression of the one or more miRNAs in the biological sample to determine if the subject is responding to treatment with the HDAC inhibitor.

[00195] In some embodiments of each or any of the above-mentioned or below- mentioned embodiments, the miRNA is one or more of miR-17, miR-20a, miR18a, miR19a, miR-19b or miR92a.

[00196] In some embodiments of each or any of the above-mentioned or below- mentioned embodiments, the miRNA is miRNA 17-92.

[00197] In some embodiments of each or any of the above-mentioned or below- mentioned embodiments, the HDAC inhibitor is a small molecule.

[00198] In some embodiments of each or any of the above-mentioned or below- mentioned embodiments, the biological sample is from a tumor.

[00199] In some embodiments of each or any of the above-mentioned or below- mentioned embodiments, the tumor is a breast or colon tumor.

[00200] In some embodiments of each or any of the above-mentioned or below- mentioned embodiments, the biological sample is from an aspirate.

[00201] In some embodiments of each or any of the above-mentioned or below- mentioned embodiments, the biological sample is from a cancer patient.

[00202] In some embodiments of each or any of the above-mentioned or below- mentioned embodiments, the subject is determined to be responding to treatment with the HDAC inhibitor where expression of the one or more miRNAs in the biological sample is elevated as compared to the control sample or is greater than the threshold.

[00203] 199 In some embodiments of each or any of the above-mentioned or below- mentioned embodiments, the subject is determined to be responding to treatment with the HDAC inhibitor where expression of the one or more miRNAs in the biological sample is reduced as compared to the control sample or is less than the threshold. [00204] In some embodiments of each or any of the above-mentioned or below- mentioned embodiments, wherein the step of assaying the biological sample for expression of one or more miRNAs is performed by in situ hybridization (ISH), Northern blot or microarray analysis.

[00205] In some embodiments of each or any of the above-mentioned or below- mentioned embodiments, the threshold is set at a level of miRNA expression above which a subject is known to respond to treatment with the HDAC inhibitor and below which a subject is known to not respond to treatment with the HDAC inhibitor.

[00206] In some embodiments of each or any of the above-mentioned or below- mentioned embodiments, the threshold is set at a level of miRNA expression below which a subject is known to respond to treatment with the HDAC inhibitor and above which a subject is known to not respond to treatment with the HDAC inhibitor.

[00207] In some embodiments of each or any of the above-mentioned or below- mentioned embodiments, the threshold is set at a level of miRNA expression above which 50%, 60%, 70%, 80%, 90%, or 95% of subject(s) respond to treatment with the HDAC inhibitor.

[00208] In some embodiments of each or any of the above-mentioned or below- mentioned embodiments, the threshold is set at a level of miRNA expression above which 50%, 60%, 70%, 80%, 90%, 95% or greater of subject(s) do not respond to treatment with the HDAC inhibitor.

[00209] In some embodiments of each or any of the above-mentioned or below- mentioned embodiments, the threshold is set at a level of miRNA expression below which 50%, 60%, 70%, 80%, 90%, 95%, or greater of subject(s) respond to treatment with the HDAC inhibitor.

[00210] In some embodiments of each or any of the above-mentioned or below- mentioned embodiments, the threshold is set at a level of miRNA expression below which 50%, 60%, 70%, 80%, 90%, 95%, or greater of subject(s) do not respond to treatment with the HDAC inhibitor.

[0021 1] In some embodiments of each or any of the above-mentioned or below- mentioned embodiments, the disease or disorder is cancer.

[00212] In some embodiments of each or any of the above-mentioned or below- mentioned embodiments, the cancer is selected from the group consisting of gastrointestinal, prostate cancer, ovarian cancer, breast cancer, head and neck cancer, lung cancer, non-small cell lung cancer, cancer of the nervous system, kidney cancer, retina cancer, skin cancer, liver cancer, pancreatic cancer, genital-urinary cancer and bladder cancer. [00213] In some embodiments of each or any of the above-mentioned or below- mentioned embodiments, the subject is a cancer patient.

[00214] The present disclosure also provides methods for treating a subject with a disease or disorder by administering to the subject a therapeutically effective amount of one or more histone deacetylase (HDAC) inhibitors, obtaining a biological sample from the subject, assaying the biological sample for expression of one or more miRNAs, determining if expression of the one or more miRNAs in the biological sample is elevated or reduced compared to a control sample or above or below a threshold;, employing the determination of the expression of the one or more miRNAs in the biological sample to determine if the subject is responding to treatment with the HDAC inhibitor, and continuing to administer to the subject a therapeutically effective amount of one or more HDAC inhibitors where the subject is determined to be responding to treatment with the HDAC inhibitor or discontinuing treatment of the HDAC inhibitor to the subject where the subject is determined to not be responding to treatment with the HDAC inhibitor.

[00215] In some embodiments of each or any of the above-mentioned or below- mentioned embodiments, the miRNA is one or more of miR-17, miR-20a, miR18a, miR19a, miR-19b or miR92a.

[00216] In some embodiments of each or any of the above-mentioned or below- mentioned embodiments, the miRNA is miRNA 17-92.

[00217] In some embodiments of each or any of the above-mentioned or below- mentioned embodiments, the HDAC inhibitor is a small molecule.

[00218] In some embodiments of each or any of the above-mentioned or below- mentioned embodiments, the biological sample is from a tumor.'

[00219] In some embodiments of each or any of the above-mentioned or below- mentioned embodiments, the tumor is a breast or colon tumor.

[00220] In some embodiments of each or any of the above-mentioned or below- mentioned embodiments, the biological sample is from an aspirate.

[00221] In some embodiments of each or any of the above-mentioned or below- mentioned embodiments, the biological sample is from a cancer patient.

[00222] In some embodiments of each or any of the above-mentioned or below- mentioned embodiments, the subject is determined to be responding to treatment with the HDAC inhibitor where expression of the one or more miRNAs in the biological sample is elevated as compared to the control sample or is greater than the threshold.

[00223] In some embodiments of each or any of the above-mentioned or below- mentioned embodiments, the subject is determined to not be responding to treatment with the HDAC inhibitor where expression of the one or more miRNAs in the biological sample is reduced as compared to the control sample or is less than the threshold.

[00224] In some embodiments of each or any of the above-mentioned or below- mentioned embodiments, the disease or disorder is cancer.

[00225] In some embodiments of each or any of the above-mentioned or below- mentioned embodiments, the cancer is selected from the group consisting of gastrointestinal cancer, prostate cancer, ovarian cancer, breast cancer, head and neck cancer, lung cancer, non-small cell lung cancer, cancer of the nervous system, kidney cancer, retina cancer, skin cancer, liver cancer, pancreatic cancer, genital-urinary cancer and bladder cancer.

[00226] In some embodiments of each or any of the above-mentioned or below- mentioned embodiments, the step of assaying the biological sample for expression of one or more miRNAs is performed by in situ hybridization (ISH), Northern blot or microarray analysis.

[00227] In some embodiments of each or any of the above-mentioned or below- mentioned embodiments, the threshold is set at a level of miRNA expression above which a subject is known to respond to treatment with the HDAC inhibitor and below which a subject is known to not respond to treatment with the HDAC inhibitor.

[00228] In some embodiments of each or any of the above-mentioned or below- mentioned embodiments, the threshold is set at a level of miRNA expression below which a subject is known to respond to treatment with the HDAC inhibitor and above which a subject is known to not respond to treatment with the HDAC inhibitor.

[00229] In some embodiments of each or any of the above-mentioned or below- mentioned embodiments, the threshold is set at a level of miRNA expression above which 50%, 60%, 70%, 80%, 90%, 95%, or greater of subject(s) respond to treatment with the HDAC inhibitor.

[00230] In some embodiments of each or any of the above-mentioned or below- mentioned embodiments, the threshold is set at a level of miRNA expression above which 50%, 60%, 70%, 80%, 90%, 95% or greater of subject(s) do not respond to treatment with the HDAC inhibitor.

[00231] In some embodiments of each or any of the above-mentioned or below- mentioned embodiments, the threshold is set at a level of miRNA expression below which 50%, 60%, 70%, 80%, 90%, 95%, or greater of subject(s) respond to treatment with the HDAC inhibitor.

[00232] In some embodiments of each or any of the above-mentioned or below- mentioned embodiments, the threshold is set at a level of miRNA expression below which 50%, 60%, 70%, 80%, 90%, 95%, or greater of subject(s) do not respond to treatment with the HDAC inhibitor.

[00233] In some embodiments of each or any of the above-mentioned or below- mentioned embodiments, the subject is a cancer patient.

[00234] In some embodiments of each or any of the above-mentioned or below- mentioned embodiments, the therapeutically effective amount of one or more HDAC inhibitors are optionally adapted for a co-treatment with radiotherapy or radio- immunotherapy.

[00235] The present disclosure also provides methods for selecting subjects for a clinical trial that are determined to be responding to a histone deacetylase (HDAC) inhibitor by administering to the subject a therapeutically effective amount of one or more histone deacetylase (HDAC) inhibitors, obtaining a biological sample from the subject, assaying the biological sample for expression of one or more miRNAs, determining if expression of the one or more miRNAs in the biological sample is elevated or reduced compared to a control sample or above or below a threshold, employing the determination of the expression of the one or more miRNAs in the biological sample to determine if the subject is responding to treatment with the HDAC inhibitor, and selecting subjects for inclusion in the clinical trial that are determined to be responding to treatment with the HDAC inhibitor or selecting subjects for inclusion in the clinical trial that are determined to not be responding to treatment with the HDAC inhibitor.

[00236] In some embodiments of each or any of the above-mentioned or below- mentioned embodiments, the miRNA is one or more of miR-17, miR-20a, miR18a, miR19a, miR-19b or miR92a.

[00237] In some embodiments of each or any of the above-mentioned or below- mentioned embodiments, the miRNA is miRNA 17-92.

[00238] In some embodiments of each or any of the above-mentioned or below- mentioned embodiments, the HDAC inhibitor is a small molecule.

[00239] In some embodiments of each or any of the above-mentioned or below- mentioned embodiments, the biological sample is from a tumor.

[00240] In some embodiments of each or any of the above-mentioned or below- mentioned embodiments, the tumor is a breast or colon tumor.

[00241] In some embodiments of each or any of the above-mentioned or below- mentioned embodiments, the biological sample is from an aspirate.

[00242] In some embodiments of each or any of the above-mentioned or below- mentioned embodiments, the biological sample is from a cancer patient. [00243] In some embodiments of each or any of the above-mentioned or below- mentioned embodiments, the subject determined to be responding to treatment with the HDAC inhibitor where expression of the one or more miRNAs in the biological sample is elevated as compared to the control sample or is greater than the threshold.

[00244] In some embodiments of each or any of the above-mentioned or below- mentioned embodiments, the subject is determined to not be responding to treatment with the HDAC inhibitor where expression of the one or more miRNAs in the biological sample is reduced as compared to the control sample or is less than the threshold.

[00245] In some embodiments of each or any of the above-mentioned or below- mentioned embodiments, the disease or disorder is cancer.

[00246] In some embodiments of each or any of the above-mentioned or below- mentioned embodiments, the cancer is selected from the group consisting of gastrointestinal cancer, prostate cancer, ovarian cancer, breast cancer, head and neck cancer, lung cancer, non-small cell lung cancer, cancer of the nervous system, kidney cancer, retina cancer, skin cancer, liver cancer, pancreatic cancer, genital-urinary cancer and bladder cancer.

[00247] In some embodiments of each or any of the above-mentioned or below- mentioned embodiments, the step of assaying the test cell for expression of one or more miRNAs is performed by in situ hybridization (ISH), Northern blot or microarray analysis.

[00248] In some embodiments of each or any of the above-mentioned or below- mentioned embodiments, the threshold is set at a level of miRNA expression above which a subject is known to respond to treatment with the HDAC inhibitor and below which a subject is known to not respond to treatment with the HDAC inhibitor.

[00249] In some embodiments of each or any of the above-mentioned or below- mentioned embodiments, the threshold is set at a level of miRNA expression below which a subject is known to respond to treatment with the HDAC inhibitor and above which a subject is known to not respond to treatment with the HDAC inhibitor.

[00250] In some embodiments of each or any of the above-mentioned or below- mentioned embodiments, the threshold is set at a level of miRNA expression above which 50%, 60%, 70%, 80%, 90%, 95%, or greater of subject(s) respond to treatment with the HDAC inhibitor.

[00251] In some embodiments of each or any of the above-mentioned or below- mentioned embodiments, the threshold is set at a level of miRNA expression above which 50%, 60%, 70%, 80%, 90%, 95% or greater of subject(s) do not respond to treatment with the HDAC inhibitor.

[00252] In some embodiments of each or any of the above-mentioned or below- mentioned embodiments, the threshold is set at a level of miRNA expression below which 50%, 60%, 70%, 80%, 90%, 95%, or greater of subject(s) respond to treatment with the HDAC inhibitor.

[00253] In some embodiments of each or any of the above-mentioned or below- mentioned embodiments, the threshold is set at a level of miRNA expression below which 50%, 60%, 70%, 80%, 90%, 95%, or greater of subject(s) do not respond to treatment with the HDAC inhibitor.

[00254] In some embodiments of each or any of the above-mentioned or below- mentioned embodiments, the subject is a cancer patient.

[00255] In some embodiments of each or any of the above-mentioned or below- mentioned embodiments, the method also includes seeking regulatory approval for the histone deacetylase (HDAC) inhibitor.

[00256] In some embodiments of each or any of the above-mentioned or below- mentioned embodiments, the clinical trial is a phase I, phase II, phase III or phase IV clinical trial.

[00257] The present disclosure also provides methods for determining if a subject with a disease or disorder is responding to treatment with a histone deacetylase (HDAC) inhibitor by obtaining a biological sample from the subject, assaying the biological sample for c-myc expression and/or c-myc amplification, determining if c-myc expression and/or c-myc amplification in the biological sample is increased or decreased as compared to a control sample or above or below a threshold, and employing the determination of c-myc expression and/or c-myc amplification in the biological sample to determine if the subject is responding to treatment with the HDAC inhibitor.

[00258] In some embodiments of each or any of the above-mentioned or below- mentioned embodiments, the HDAC inhibitor is a small molecule.

[00259] In some embodiments of each or any of the above-mentioned or below- mentioned embodiments, the biological sample is from a tumor.

[00260] In some embodiments of each or any of the above-mentioned or below- mentioned embodiments, the tumor is from a breast or colon tumor.

[00261] In some embodiments of each or any of the above-mentioned or below- mentioned embodiments, the biological sample is from an aspirate.

[00262] In some embodiments of each or any of the above-mentioned or below- mentioned embodiments, the biological sample is from a cancer patient.

[00263] In some embodiments of each or any of the above-mentioned or below- mentioned embodiments, the subject is predicted to be responsive to the HDAC inhibitor where c-myc expression and/or c-myc amplification is elevated in the biological sample as compared to the control sample or is greater than the threshold. [00264] In some embodiments of each or any of the above-mentioned or below- mentioned embodiments, the subject is predicted to not be responsive to the HDAC inhibitor where c-myc expression and/or c-myc amplification is reduced in the biological sample as compared to the control sample or is less than the threshold.

[00265] In some embodiments of each or any of the above-mentioned or below- mentioned embodiments, the step of assaying the biological sample for c-myc expression and/or c-myc amplification is performed by in situ hybridization (ISH), Northern blot or microarray analysis.

[00266] In some embodiments of each or any of the above-mentioned or below- mentioned embodiments, the threshold is set at a level of c-myc expression and/or c-myc amplification above which a subject is known to respond to treatment with the HDAC inhibitor and below which a subject is known to not respond to treatment with the HDAC inhibitor.

[00267] In some embodiments of each or any of the above-mentioned or below- mentioned embodiments, the threshold is set at a level of c-myc expression and/or c-myc amplification below which a subject is known to respond to treatment with the HDAC inhibitor and above which a subject is known to not respond to treatment with the HDAC inhibitor.

[00268] In some embodiments of each or any of the above-mentioned or below- mentioned embodiments, the threshold is set at a level of c-myc expression and/or c-myc amplification above which 50%, 60%, 70%, 80%, 90%, or 95% of subject(s) respond to treatment with the HDAC inhibitor.

[00269] In some embodiments of each or any of the above-mentioned or below- mentioned embodiments, the threshold is set at a level of c-myc expression and/or c-myc amplification above which 50%, 60%, 70%, 80%, 90%, or 95% of subject(s) do not respond to treatment with the HDAC inhibitor.

[00270] In some embodiments of each or any of the above-mentioned or below- mentioned embodiments, the threshold is set at a level of c-myc expression and/or c-myc amplification below which 50%, 60%, 70%, 80%, 90%, or 95% of subject(s) respond to treatment with the HDAC inhibitor.

[00271] In some embodiments of each or any of the above-mentioned or below- mentioned embodiments, the threshold is set at a level of c-myc expression and/or c-myc amplification below which 50%, 60%, 70%, 80%, 90%, or 95% of subject(s) do not respond to treatment with the HDAC inhibitor.

[00272] In some embodiments of each or any of the above-mentioned or below- mentioned embodiments, the disease or disorder is cancer. [00273] In some embodiments of each or any of the above-mentioned or below- mentioned embodiments, the cancer is selected from the group consisting of gastrointestinal, prostate cancer, ovarian cancer, breast cancer, head and neck cancer, lung cancer, non-small cell lung cancer, cancer of the nervous system, kidney cancer, retina cancer, skin cancer, liver cancer, pancreatic cancer, genital-urinary cancer and bladder cancer.

[00274] In some embodiments of each or any of the above-mentioned or below- mentioned embodiments, the subject is a cancer patient.

[00275] The present disclosure also provides methods for treating a subject with a disease or disorder by administering to the subject a therapeutically effective amount of one or more histone deacetylase (HDAC) inhibitors, obtaining a biological sample from a subject, assaying the biological sample for c-myc expression and/or c-myc amplification, determining if c-myc expression and/or c-myc amplification in the cell is elevated or reduced compared to a control sample or above or below a threshold;, employing the determination of c-myc expression and/or c-myc amplification in the biological sample to determine if the subject is responding to treatment with the HDAC inhibitor, and continuing to administer to the subject a therapeutically effective amount of one or more HDAC inhibitors where the subject is determined to be responding to treatment with the HDAC inhibitor or discontinuing treatment of the HDAC inhibitor to the subject where the subject is determined to not be responding to treatment with the HDAC inhibitor.

[00276] In some embodiments of each or any of the above-mentioned or below- mentioned embodiments, the HDAC inhibitor is a small molecule.

[00277] In some embodiments of each or any of the above-mentioned or below- mentioned embodiments, the biological sample is from a tumor.

[00278] In some embodiments of each or any of the above-mentioned or below- mentioned embodiments, the tumor is from a breast or colon tumor.

[00279] In some embodiments of each or any of the above-mentioned or below- mentioned embodiments, the biological sample is from an aspirate.

[00280] In some embodiments of each or any of the above-mentioned or below- mentioned embodiments, the biological sample is from a cancer patient.

[00281] In some embodiments of each or any of the above-mentioned or below- mentioned embodiments, the subject is predicted to be responsive to the HDAC inhibitor where c-myc expression and/or c-myc amplification is elevated in the biological sample as compared to the control sample or is greater than the threshold.

[00282] In some embodiments of each or any of the above-mentioned or below- mentioned embodiments, the subject is predicted to not be responsive to the HDAC inhibitor where c-myc expression and/or c-myc amplification is reduced in the biological sample as compared to the control sample or is less than the threshold.

[00283] In some embodiments of each or any of the above-mentioned or below- mentioned embodiments, the disease or disorder is cancer.

[00284] In some embodiments of each or any of the above-mentioned or below- mentioned embodiments, the cancer is selected from the group consisting of gastrointestinal cancer, prostate cancer, ovarian cancer, breast cancer, head and neck cancer, lung cancer, non-small cell lung cancer, cancer of the nervous system, kidney cancer, retina cancer, skin cancer, liver cancer, pancreatic cancer, genital-urinary cancer and bladder cancer.

[00285] In some embodiments of each or any of the above-mentioned or below- mentioned embodiments, the step of assaying the test cell for c-myc expression and/or c- myc amplification is performed by in situ hybridization (ISH), Northern blot or microarray analysis.

[00286] In some embodiments of each or any of the above-mentioned or below- mentioned embodiments, the threshold is set at a level of c-myc expression and/or c-myc amplification above which a subject is known to respond to treatment with the HDAC inhibitor and below which a subject is known to not respond to treatment with the HDAC inhibitor.

[00287] In some embodiments of each or any of the above-mentioned or below- mentioned embodiments, the threshold is set at a level of c-myc expression and/or c-myc amplification below which a subject is known to respond to treatment with the HDAC inhibitor and above which a subject is known to not respond to treatment with the HDAC inhibitor.

[00288] In some embodiments of each or any of the above-mentioned or below- mentioned embodiments, the threshold is set at a level of c-myc expression and/or c-myc amplification above which 50%, 60%, 70%, 80%, 90%, or 95% of subject(s) respond to treatment with the HDAC inhibitor.

[00289] In some embodiments of each or any of the above-mentioned or below- mentioned embodiments, the threshold is set at a level of c-myc expression and/or c-myc amplification above which 50%, 60%, 70%, 80%, 90%, or 95% of subject(s) do not respond to treatment with the HDAC inhibitor.

[00290] In some embodiments of each or any of the above-mentioned or below- mentioned embodiments, the threshold is set at a level of c-myc expression and/or c-myc amplification below which 50%, 60%, 70%, 80%, 90%, or 95% of subject(s) respond to treatment with the HDAC inhibitor.

[00291] In some embodiments of each or any of the above-mentioned or below- mentioned embodiments, the threshold is set at a level of c-myc expression and/or c-myc amplification below which 50%, 60%, 70%, 80%, 90%, or 95% of subject(s) do not respond to treatment with the HDAC inhibitor.

[00292] In some embodiments of each or any of the above-mentioned or below- mentioned embodiments, the subject is a cancer patient.

[00293] In some embodiments of each or any of the above-mentioned or below- mentioned embodiments, the therapeutically effective amount of one or more HDAC inhibitors are optionally adapted for a co-treatment with radiotherapy or radio- immunotherapy.

[00294] The present disclosure also provides methods for selecting subjects for a clinical trial that are determined to be responding to a histone deacetylase (HDAC) inhibitor by administering to the subject a therapeutically effective amount of one or more histone deacetylase (HDAC) inhibitors, obtaining a biological sample from the subjects, assaying the biological samples obtained from the subjects for c-myc expression and/or c-myc amplification, determining if c-myc expression and/or amplification in the biological sample is elevated or reduced compared to a control sample or above or below a threshold, employing the determination of the c-myc expression and/or amplification in the biological sample to determine if the subject is responding to treatment with the HDAC inhibitor, and selecting subjects for inclusion in the clinical trial that are determined to be responding to treatment with the HDAC inhibitor or selecting subjects for inclusion in the clinical trial that are determined to not be responding to treatment with the HDAC inhibitor.

[00295] In some embodiments of each or any of the above-mentioned or below- mentioned embodiments, the HDAC inhibitor is a small molecule.

[00296] In some embodiments of each or any of the above-mentioned or below- mentioned embodiments, the biological sample is from a tumor.

[00297] In some embodiments of each or any of the above-mentioned or below- mentioned embodiments, the tumor is from a breast or colon tumor.

[00298] In some embodiments of each or any of the above-mentioned or below- mentioned embodiments, the biological sample is from an aspirate.

[00299] In some embodiments of each or any of the above-mentioned or below- mentioned embodiments, the biological sample is from a cancer patient.

[00300] In some embodiments of each or any of the above-mentioned or below- mentioned embodiments, the subject is predicted to be responsive to the HDAC inhibitor where c-myc expression and/or c-myc amplification is elevated in the biological sample as compared to the control sample or is greater than the threshold.

[00301] In some embodiments of each or any of the above-mentioned or below- mentioned embodiments, the subject is predicted to not be responsive to the HDAC inhibitor where c-myc expression and/or c-myc amplification is reduced in the biological sample as compared to the control sample or is less than the threshold.

[00302] In some embodiments of each or any of the above-mentioned or below- mentioned embodiments, the disease or disorder is cancer.

[00303] In some embodiments of each or any of the above-mentioned or below- mentioned embodiments, the cancer is selected from the group consisting of gastrointestinal cancer, prostate cancer, ovarian cancer, breast cancer, head and neck cancer, lung cancer, non-small cell lung cancer, cancer of the nervous system, kidney cancer, retina cancer, skin cancer, liver cancer, pancreatic cancer, genital-urinary cancer and bladder cancer.

[00304] In some embodiments of each or any of the above-mentioned or below- mentioned embodiments, the step of assaying the test cell for c-myc expression and/or amplification is performed by in situ hybridization (ISH), Northern blot or microarray analysis.

[00305] In some embodiments of each or any of the above-mentioned or below- mentioned embodiments, the threshold is set at a level of c-myc expression and/or c-myc amplification above which a subject is known to respond to treatment with the HDAC inhibitor and below which a subject is known to not respond to treatment with the HDAC inhibitor.

[00306] In some embodiments of each or any of the above-mentioned or below- mentioned embodiments, the threshold is set at a level of c-myc expression and/or c-myc amplification below which a subject is known to respond to treatment with the HDAC inhibitor and above which a subject is known to not respond to treatment with the HDAC inhibitor.

[00307] In some embodiments of each or any of the above-mentioned or below- mentioned embodiments, the threshold is set at a level of c-myc expression and/or c-myc amplification above which 50%, 60%, 70%, 80%, 90%, or 95% of subject(s) respond to treatment with the HDAC inhibitor.

[00308] In some embodiments of each or any of the above-mentioned or below- mentioned embodiments, the threshold is set at a level of c-myc expression and/or c-myc amplification above which 50%, 60%, 70%, 80%, 90%, or 95% of subject(s) do not respond to treatment with the HDAC inhibitor.

[00309] In some embodiments of each or any of the above-mentioned or below- mentioned embodiments, the threshold is set at a level of c-myc expression and/or c-myc amplification below which 50%, 60%, 70%, 80%, 90%, or 95% of subject(s) respond to treatment with the HDAC inhibitor.

[00310] In some embodiments of each or any of the above-mentioned or below- mentioned embodiments, the threshold is set at a level of c-myc expression and/or c-myc amplification below which 50%, 60%, 70%, 80%, 90%, or 95% of subject(s) do not respond to treatment with the HDAC inhibitor.

[0031 1] In some embodiments of each or any of the above-mentioned or below- mentioned embodiments, the subject is a cancer patient.

[00312] In some embodiments of each or any of the above-mentioned or below- mentioned embodiments, the method includes seeking regulatory approval for the histone deacetylase (HDAC) inhibitor.

[00313] In some embodiments of each or any of the above-mentioned or below- mentioned embodiments, the clinical trial is a phase I, phase II, phase III or phase IV clinical trial.

BRIEF DESCRIPTION OF THE DRAWINGS

[00314] The foregoing summary, as well as the following detailed description of the disclosure, will be better understood when read in conjunction with the appended figures. For the purpose of illustrating the disclosure, shown in the figures are embodiments which are presently preferred. It should be understood, however, that the disclosure is not limited to the precise arrangements, examples and instrumentalities shown.

[00315] Figure 1 : Western blot showing acetyl histone H3 and p21 levels in MDA- MB-231 and MCF-7 cells treated with varying concentrations of SAHA, MS-275 or LAQ824.

[00316] Figure 2: MiRNA microarray data indicating expression of members of the MIR-17-92 cluster and its homologues in MDA-MB-231 and MCF-7 cells treated with HDACIs.

[00317] Figure 3: Graphical representation of miR-17, -18A, -19A, and -20A expression in MBA-MB-231 (panel A) and MCF-7 cells (panel B) treated with SAHA, MS- 275, or LAQ824.

[00318] Figure 4: MiR-18A, -19A and -20A expression in breast, CNS, colon, leukemia, melanoma, lung, ovarian, prostate and renal cells lines.

[00319] Figure 5: Table showing approximate copy number of c-myc in selected cell lines.

[00320] Figure 6: Plot of gene expression miR-17, -18, -19, and -20A gene expression in 231 m AU565, COLO205, H460, HCT1 16, MCF-7 and SW620 cells.

[00321] Figure 7: Graphical representation of the relative expression of miR-18, - 19 and -20 in MCF-7, MDA-MB-231 , AU565 and SW620 cells.

[00322] Figure 8: Gl₅₀ of SAHA, MS-275 or LAQ824 in MCF-7, MDA-MB-231 cells.

[00323] Figure 9: Gl₅₀ of HCACIs in MCF-7 and MDS-MB-231 cells versus increasing expression of miR-17-92 cluster. [00324] Figure 10: Gl₅₀ of SAHA in c-myc amplified cells and c-myc unamplified cells.

[00325] Figure 1 1 : Gl₅₀ of LAQ824 in c-myc amplified cells and c-myc unamplified cells.

[00326] Figure 12: Western blot for PARP cleavage in AU565, SW620, MCF-7 and MDA-MB-231 cells treated SAHA or LAQ824.

[00327] Figure 13: Expression of miR-17~92 in c-myc amplified AU565 and SW620 cells treated with SAHA or LAQ824.

[00328] Figure 14: Western blot for c-myc, Bim, acetyl-H3 and p21 expression in SW620 and AU565 cells treated with SAHA or LAQ824 (Panel A). Western blot for c-myc, Bim, acetyl-H3 and p21 expression in MCF-7 and MDA-MB-231 cells treated with SAHA or LAQ824 (Panel B).

[00329] Figure 15: RT-PCT analysis of miR-17-92 expression in c-myc unamplified and myc amplified cells.

[00330] Figure 16: Bim expression was measured by RT-PCR in AU565 and SW620 cells transfected with antagomiRs against miR-18, miR-19, or miR-20.

DETAILED DESCRIPTION

[00331] Histone deacetlyase (HDAC) inhibitors (referred to as HDACIs) are often used in the treatment of diseases and/or disorders such as cancer, neurodegenerative diseases, psychiatric disorders, inflammation, autoimmune diseases and metabolic diseases. However, some subjects respond to treatment with a histone deacetylase inhibitor (HDACI) while other subjects do not respond to such treatment. Thus, biomarkers and methods are desired which can be used to predict or determine whether a particular subject will be responsive (or is responding) to treatment with a HDACI, or whether the subject is predicted to not be responsive (or is determined to not be responding) to treatment with the HDACI. Notably, the inventors of the instant application have unexpectedly found that HDACIs down-regulate the expression of c-myc which in turn down-regulates the expression of the MIR 17-92 cluster which in turn leads to the up-regulation of its pro-apoptotic target bim and cellular death in tumor cells (e.g., solid tumor cells such as breast cancer cells). Additionally, the inventors have unexpectedly shown that one or more of MiR-17, MiR-18A, Mir18B, Mir19A, Mir19B1 , Mir19B2, Mir20A, Mir92A1 , Mir92A2, Mir106A or Mir20B (or their homologues) and/or c-myc and/or possession of a c-myc amplification (e.g., 3, 4, 5, 6 ,7, 8, 9 or 10 copies of c-myc per cell; myc amplified cells) in a cell and/or biological sample that is greater than the expression of one or more of miR-17, miR-20a, miR18a, miR19a, miR-19b or miR92a and/or c-myc expression and/or c-myc amplification (e.g., c-myc gene copy number) in a control cell or biological sample correlates with sensitivity (e.g., responsiveness) to a HDACI. Accordingly, the methods of the instant application may be used to successfully predict whether a subject will be responsive to treatment with a HDACI or determine whether a subject is responding to treatment with a HDACI.

[00332] The present disclosure provides methods for predicting sensitivity of a test cell to treatment with a histone deacetylase (HDAC) inhibitor by obtaining a test cell; assaying the test cell for expression of one or more miRNAs (e.g., one or more of miR-17, miR-20a, miR18a, miR19a, miR-19b or miR92a; or their homologues); determining if expression of the one or more miRNAs in the test cell is elevated or reduced compared to a control cell or above or below a threshold; and employing the determination of the expression of the one or more miRNAs in the test cell to predict sensitivity of the test cell to the HDAC inhibitor. The test cell may be predicted to be sensitive to the HDAC inhibitor where expression of the one or more miRNAs in the test cell is elevated as compared to expression of the one or more miRNAs in the control cell or is above the threshold. Alternatively, the test cell may be predicted to not be sensitive to the HDAC inhibitor where expression of the one or more miRNAs in the test cell is reduced as compared to expression of the one or more miRNAs in the control cell or is less than the threshold. The threshold may be set at a level of miRNA expression above which a cell is known to be sensitive to treatment with the HDAC inhibitor and below which a cell is known to not be sensitive to treatment with the HDAC inhibitor. In some embodiments, the threshold may be set at a level of miRNA expression above which 50%, 60%, 70%, 80%, 90%, or 95% of cells respond to treatment with a HDAC or at a level of miRNA expression below which 50%, 60%, 70%, 80%, 90%, or 95% of cells do not respond to treatment with a HDAC inhibitor.

[00333] The present disclosure also provides methods for predicting responsiveness of a subject with a disease or disorder to treatment with a histone deacetylase (HDAC) inhibitor by obtaining a biological sample from the subject; assaying the biological sample for expression of one or more miRNAs (e.g., one or more of miR-17, miR- 20a, miR18a, miR19a, miR-19b or miR92a; or their homologues); determining if expression of the one or more miRNAs in the cell is elevated or reduced compared to a control sample or above or below a threshold; and employing the determination of the expression of the one or more miRNAs in the biological sample to predict responsiveness of the subject to the HDAC inhibitor. The subject may be predicted to be responsive to the HDAC inhibitor where expression of the one or more miRNAs in the biological sample is elevated as compared to the control sample or is greater than the threshold. Alternatively, the subject may be predicted to not be responsive to the HDAC inhibitor where expression of the one or more miRNAs in the biological sample is reduced as compared to the control sample or is less than the threshold. The threshold may be set at a level of miRNA expression above which a subject is known to respond to treatment with the HDAC inhibitor and below which a subject is known to not respond to treatment with the HDAC inhibitor. In some embodiments, the threshold is set at a level of miRNA expression above which 50%, 60%, 70%, 80%, 90%, or 95% of subject(s) respond to treatment with the HDAC inhibitor. In some embodiments, the threshold is set at a level of miRNA expression below which 50%, 60%, 70%, 80%, 90%, or 95% of subject(s) do not respond to treatment with the HDAC inhibitor

[00334] The present disclosure also provides methods for treating a subject with a disease or disorder by obtaining a biological sample from a subject; assaying the biological sample for expression of one or more miRNAs (e.g., one or more of miR-17, miR-20a, miR18a, miR19a, miR-19b or miR92a; or their homologues); determining if expression of the one or more miRNAs in the biological sample is elevated or reduced compared to a control sample or above or below a threshold; employing the determination of the expression of the one or more miRNAs in the biological sample to predict responsiveness of the subject to the HDAC inhibitor; and administering to the subject a therapeutically effective amount of a therapeutic regimen including, for example, one or more histone deacetylase (HDAC) inhibitors where the subject is predicted to be responsive to the HDAC inhibitor. The subject may be predicted to be responsive to the HDAC inhibitor where expression of the one or more miRNAs in the biological sample is elevated as compared to the control sample or is greater than the threshold. Alternatively, the subject may be predicted to not be responsive to the HDAC inhibitor where expression of the one or more miRNAs in the biological sample is reduced as compared to the control sample or is less than the threshold. The threshold may be set at a level of miRNA expression above which a subject is known to respond to treatment with the HDAC inhibitor and below which a subject is known to not respond to treatment with the HDAC inhibitor. In some embodiments, the threshold is set at a level of miRNA expression above which 50%, 60%, 70%, 80%, 90%, or 95% of subject(s) respond to treatment with the HDAC inhibitor. In some embodiments, the threshold is set at a level of miRNA expression below which 50%, 60%, 70%, 80%, 90%, or 95% of subject(s) do not respond to treatment with the HDAC inhibitor.

[00335] The present disclosure also provides methods for selecting subjects for a clinical trial that are responsive to treatment with a histone deacetylase (HDAC) inhibitor by obtaining a biological sample from the subjects; assaying the biological samples obtained from the subjects for expression of one or more miRNAs (e.g., one or more of miR-17, miR- 20a, miR18a, miR19a, miR-19b or miR92a; or their homologues); determining if expression of the one or more miRNAs in the biological sample is elevated or reduced compared to a control sample or above or below a threshold; employing the determination of the expression of the one or more miRNAs in the biological sample to predict responsiveness of the subject to the HDAC inhibitor; and selecting subjects for inclusion in a clinical trial that are responsive to the HDAC inhibitor. The subject may be predicted to be responsive to the HDAC inhibitor where expression of the one or more miRNAs in the biological sample is elevated as compared to the control sample or is greater than the threshold. Alternatively, the subject may be predicted to not be responsive to the HDAC inhibitor where expression of the one or more miRNAs in the biological sample is reduced as compared to the control sample or is less than the threshold. The threshold may be set at a level of miRNA expression above which a subject is known to respond to treatment with the HDAC inhibitor and below which a subject is known to not respond to treatment with the HDAC inhibitor. In some embodiments, the threshold is set at a level of miRNA expression above which 50%, 60%, 70%, 80%, 90%, or 95% of subject(s) respond to treatment with the HDAC inhibitor. In some embodiments, the threshold is set at a level of miRNA expression below which 50%, 60%, 70%, 80%, 90%, or 95% of subject(s) do not respond to treatment with the HDAC inhibitor.

[00336] The present disclosure also provides methods for screening a test cell for sensitivity to treatment with a histone deacetylase (HDAC) inhibitor by obtaining a test cell; assaying the test cell for expression of one or more miRNAs (e.g., one or more of miR-17, miR-20a, miR18a, miR19a, miR-19b or miR92a; or their homologues); and determining if expression of the one or more miRNAs in the test cell is elevated or reduced compared to a control cell or above or below a threshold, wherein the test cell is determined to be sensitive to the HDAC inhibitor where expression of the one or more miRNAs in the test cell is elevated as compared to expression of the one or more miRNAs in the control cell or is above the threshold and wherein the test cell is determined to not be sensitive to the HDAC inhibitor where expression of the one or more miRNAs in the test cell is reduced as compared to expression of the one or more miRNAs in the control cell or is less than the threshold. The test cell may be predicted to be sensitive to the HDAC inhibitor where expression of the one or more miRNAs in the test cell is elevated as compared to expression of the one or more miRNAs in the control cell or is above the threshold. Alternatively, the test cell may be predicted to not be sensitive to the HDAC inhibitor where expression of the one or more miRNAs in the test cell is reduced as compared to expression of the one or more miRNAs in the control cell or is less than the threshold. The threshold may be set at a level of miRNA expression above which a cell is known to be sensitive to treatment with the HDAC inhibitor and below which a cell is known to not be sensitive to treatment with the HDAC inhibitor. In some embodiments, the threshold may be set at a level of miRNA expression above which 50%, 60%, 70%, 80%, 90%, or 95% of cells respond to treatment with a HDAC and/or at a level of miRNA expression below which 50%, 60%, 70%, 80%, 90%, or 95% of cells do not respond to treatment with a HDAC inhibitor.

[00337] The present disclosure also provides methods for predicting sensitivity of a test cell to treatment with a histone deacetylase (HDAC) inhibitor by obtaining a test cell; assaying the test cell for expression of c-myc and/or a c-myc amplification (e.g., 3, 4, 5, 6 ,7, 8, 9 or 10 copies of c-myc per cell); determining if c-myc is expressed and/or amplified in the test cell as compared to a control cell or above or below a threshold; and employing the determination of c-myc expression and/or amplification in the test cell to predict sensitivity of the test cell to the HDAC inhibitor. The test cell may be predicted to be sensitive to the HDAC inhibitor where c-myc expression and/or amplification in the test cell is elevated as compared to c-myc expression and/or c-myc amplification in the control cell or is above the threshold. Alternatively, the test cell may be predicted to not be sensitive to the HDAC inhibitor where c-myc expression and/or amplification in the test cell is reduced as compared to c-myc expression and/or c-myc amplification in the control cell or is less than the threshold. The threshold may be set at a level of c-myc expression and/or c-myc amplification above which a cell is known to be sensitive to treatment with the HDAC inhibitor and below which a cell is known to not be sensitive to treatment with the HDAC inhibitor. In some embodiments, the threshold may be set at a level of c-myc expression and/or c-myc amplification above which 50%, 60%, 70%, 80%, 90%, or 95% of cells respond to treatment with a HDAC and/or at a level of c-myc expression and/or c-myc amplification below which 50%, 60%, 70%, 80%, 90%, or 95% of cells do not respond to treatment with a HDAC inhibitor.

[00338] The present disclosure also provides methods for predicting responsiveness of a subject with a disease or disorder to treatment with a histone deacetylase (HDAC) inhibitor by obtaining a biological sample from the subject; assaying the biological sample for c-myc expression and/or a c-myc amplification (e.g., 3, 4, 5, 6 ,7, 8, 9 or 10 copies of c-myc per cell); determining if c-myc is expressed and/or amplified in the biological sample as compared to a control sample or above or below a threshold; and employing the determination of c-myc expression and/or c-myc amplification in the biological sample to predict responsiveness of the subject to the HDAC inhibitor. The subject may be predicted to be responsive to the HDAC inhibitor where c-myc expression and/or c-myc amplification in the biological sample is elevated as compared to the control sample or is greater than the threshold. Alternatively, the subject may be predicted to not be responsive to the HDAC inhibitor where level of c-myc expression and/or c-myc amplification in the biological sample is reduced as compared to the control sample or is less than the threshold. The threshold may be set at a level of c-myc expression and/or c-myc amplification above which a subject is known to respond to treatment with the HDAC inhibitor and below which a subject is known to not respond to treatment with the HDAC inhibitor. In some embodiments, the threshold is set at a level of c-myc expression and/or c-myc amplification above which 50%, 60%, 70%, 80%, 90%, or 95% of subject(s) respond to treatment with the HDAC inhibitor. In some embodiments, the threshold is set at a level of c-myc expression and/or c- myc amplification below which 50%, 60%, 70%, 80%, 90%, or 95% of subject(s) do not respond to treatment with the HDAC inhibitor.

[00339] The present disclosure also provides methods for treating a subject with a disease or disorder by obtaining a biological sample from a subject; assaying the biological sample for c-myc expression and/or a c-myc amplification (e.g., 3, 4, 5, 6 ,7, 8, 9 or 10 copies of c-myc per cell); determining if c-myc expression and/or c-myc amplification in the cell is elevated or reduced compared to a control sample or above or below a threshold; employing the determination of c-myc expression and/or c-myc amplification in the biological sample to predict responsiveness of the subject to the HDAC inhibitor; and administering to the subject a therapeutic regimen including, for example, a therapeutically effective amount of one or more histone deacetylase (HDAC) inhibitors where the subject is predicted to be responsive to the HDAC inhibitor. The subject may be predicted to be responsive to the HDAC inhibitor where c-myc expression and/or c-myc amplification in the biological sample is elevated as compared to the control sample or is greater than the threshold. Alternatively, the subject may be predicted to not be responsive to the HDAC inhibitor where level of c- myc expression and/or c-myc amplification in the biological sample is reduced as compared to the control sample or is less than the threshold. The threshold may be set at a level of c- myc expression and/or c-myc amplification above which a subject is known to respond to treatment with the HDAC inhibitor and below which a subject is known to not respond to treatment with the HDAC inhibitor. In some embodiments, the threshold is set at a level of c- myc expression and/or c-myc amplification above which 50%, 60%, 70%, 80%, 90%, or 95% of subject(s) respond to treatment with the HDAC inhibitor. In some embodiments, the threshold is set at a level of c-myc expression and/or c-myc amplification below which 50%, 60%, 70%, 80%, 90%, or 95% of subject(s) do not respond to treatment with the HDAC inhibitor.

[00340] The present disclosure also provides methods for selecting subjects for a clinical trial that are responsive to treatment with a histone deacetylase (HDAC) inhibitor by obtaining a biological sample from the subjects; assaying the biological samples obtained from the subjects for c-myc expression and/or c-myc amplification (e.g., 3, 4, 5, 6 ,7, 8, 9 or 10 copies of c-myc per cell); determining if c-myc expression and/or c-myc amplification in the biological sample is elevated or reduced compared to a control sample or above or below a threshold; employing the determination of the c-myc expression and/or c-myc amplification in the biological sample to predict responsiveness of the subject to the HDAC inhibitor; and selecting subjects for inclusion in a clinical trial that are responsive to the HDAC inhibitor. The subject may be predicted to be responsive to the HDAC inhibitor where c-myc expression and/or c-myc amplification in the biological sample is elevated as compared to the control sample or is greater than the threshold. Alternatively, the subject may be predicted to not be responsive to the HDAC inhibitor where level of c-myc expression and/or c-myc amplification in the biological sample is reduced as compared to the control sample or is less than the threshold. The threshold may be set at a level of c- myc expression and/or c-myc amplification above which a subject is known to respond to treatment with the HDAC inhibitor and below which a subject is known to not respond to treatment with the HDAC inhibitor. In some embodiments, the threshold is set at a level of c- myc expression and/or c-myc amplification above which 50%, 60%, 70%, 80%, 90%, or 95% of subject(s) respond to treatment with the HDAC inhibitor. In some embodiments, the threshold is set at a level of c-myc expression and/or c-myc amplification below which 50%, 60%, 70%, 80%, 90%, or 95% of subject(s) do not respond to treatment with the HDAC inhibitor.

[00341] The present disclosure also provides methods for screening a test cell for sensitivity to treatment with a histone deacetylase (HDAC) inhibitor by obtaining a test cell; assaying the test cell for c-myc expression and/or a c-myc amplification (e.g., 3, 4, 5, 6 ,7, 8, 9 or 10 copies of c-myc per cell); and determining if c-myc expression and/or c-myc amplification in the test cell is elevated or reduced compared to a control cell or above or below a threshold, wherein the test cell is determined to be sensitive to the HDAC inhibitor where c-myc expression and/or c-myc amplification in the test cell is elevated as compared to the level of c-myc expression and/or c-myc amplification in the control cell or is above the threshold and wherein the test cell is determined to not be sensitive to the HDAC inhibitor where the level of c-myc expression and/or c-myc amplification in the test cell is reduced as compared to the level of c-myc expression and/or c-myc amplification in the control cell or is less than the threshold. The test cell may be predicted to be sensitive to the HDAC inhibitor where the level of c-myc expression and/or c-myc amplification in the test cell is elevated as compared to the level of c-myc expression and/or c-myc amplification in the control cell or is above the threshold. Alternatively, the test cell may be predicted to not be sensitive to the HDAC inhibitor where the level of c-myc expression and/ or c-myc amplification in the test cell is reduced as compared to the level of c-myc expression and/or c-myc amplification in the control cell or is less than the threshold. The threshold may be set at a level of c-myc expression and/or c-myc amplification above which a cell is known to be sensitive to treatment with the HDAC inhibitor and below which a cell is known to not be sensitive to treatment with the HDAC inhibitor. In some embodiments, the threshold may be set at a level of c-myc expression and/or c-myc amplification above which 50%, 60%, 70%, 80%, 90%, or 95% of cells respond to treatment with a HDAC and/or at a level of c-myc expression and/or c-myc amplification below which 50%, 60%, 70%, 80%, 90%, or 95% of cells do not respond to treatment with a HDAC inhibitor.

[00342] The present disclosure provides methods for predicting sensitivity of a test cell to treatment with a histone deacetylase (HDAC) inhibitor by obtaining a test cell; assaying the test cell for expression of one or more miRNAs (e.g., one or more of miR-17, miR-20a, miR18a, miR19a, miR-19b or miR92a; or their homologues) and/or c-myc and/or presence of a c-myc amplification (e.g., 3, 4, 5, 6 ,7, 8, 9 or 10 copies of c-myc per cell); determining if expression of the one or more miRNAs and/or c-myc and/or c-myc amplification in the test cell is elevated or reduced compared to a control cell or above or below a threshold; and employing the determination of the expression of the one or more miRNAs and/or c-myc and/or c-myc amplification in the test cell to predict sensitivity of the test cell to the HDAC inhibitor. The test cell may be predicted to be sensitive to the HDAC inhibitor where expression of the one or more miRNAs and/or c-myc and/or c-myc amplification in the test cell is elevated as compared to expression of the one or more miRNAs and/or c-myc and/or c-myc amplification in the control cell or is above the threshold. Alternatively, the test cell may be predicted to not be sensitive to the HDAC inhibitor where expression of the one or more miRNAs and/or c-myc and/or c-myc amplification in the test cell is reduced as compared to expression of the one or more miRNAs and c-myc and/or c- myc amplification in the control cell or is less than the threshold. The threshold may be set at a level of miRNA and/or c-myc expression and/or c-myc amplification above which a cell is known to be sensitive to treatment with the HDAC inhibitor and below which a cell is known to not be sensitive to treatment with the HDAC inhibitor. In some embodiments, the threshold may be set at a level of miRNA and/or c-myc expression and/or c-myc amplification above which 50%, 60%, 70%, 80%, 90%, or 95% of cells respond to treatment with a HDAC and/or at a level of miRNA and/or c-myc expression and/or c-myc amplification below which 50%, 60%, 70%, 80%, 90%, or 95% of cells do not respond to treatment with a HDAC inhibitor.

[00343] The present disclosure also provides methods for predicting responsiveness of a subject with a disease or disorder to treatment with a histone deacetylase (HDAC) inhibitor by obtaining a biological sample from the subject; assaying the biological sample for expression of one or more miRNAs (e.g., one or more of miR-17, miR- 20a, miR18a, miR19a, miR-19b or miR92a; or their homologues) and/or c-myc and/or c-myc amplification (e.g., 3, 4, 5, 6 ,7, 8, 9 or 10 copies of c-myc per cell); determining if expression of the one or more miRNAs and/or c-myc in the cell is elevated or reduced compared to a control sample or above or below a threshold; determining if c-myc is amplified in the biological sample as compared to a control sample or above or below a threshold; and employing the determination of the expression of the one or more miRNAs and/or c-myc and/or c-myc amplification in the biological sample to predict responsiveness of subject to the HDAC inhibitor. The subject may be predicted to be responsive to the HDAC inhibitor where expression of the one or more miRNAs and/or c-myc and/or c-myc amplification in the biological sample is elevated as compared to the control sample or is greater than the threshold. Alternatively, the subject may be predicted to not be responsive to the HDAC inhibitor where expression of the one or more miRNAs and/or c-myc and/or c-myc amplification in the biological sample is reduced as compared to the control sample or is less than the threshold. The threshold may be set at a level of miRNA and/or c-myc and/or c- myc amplification above which a subject is known to respond to treatment with the HDAC inhibitor and below which a subject is known to not respond to treatment with the HDAC inhibitor. In some embodiments, the threshold is set at a level of miRNA and/or c-myc expression and/or c-myc amplification above which 50%, 60%, 70%, 80%, 90%, or 95% of subject(s) respond to treatment with the HDAC inhibitor. In some embodiments, the threshold is set at a level of miRNA and/or c-myc and/or c-myc amplification below which 50%, 60%, 70%, 80%, 90%, or 95% of subject(s) do not respond to treatment with the HDAC inhibitor.

[00344] The present disclosure also provides methods for treating a subject with a disease or disorder by obtaining a biological sample from a subject; assaying the biological sample for expression of one or more miRNAs (e.g., one or more of miR-17, miR-20a, miR18a, miR19a, miR-19b or miR92a; or their homologues) and/or c-myc and/or c-myc amplification (e.g., 3, 4, 5, 6 ,7, 8, 9 or 10 copies of c-myc per cell); determining if expression of the one or more miRNAs and/or c-myc in the cell is elevated or reduced compared to a control sample or above or below a threshold; determining if c-myc is amplified in the biological sample as compared to a control sample or above or below a threshold; employing the determination of the expression of the one or more miRNAs and/or c-myc and/or c-myc amplification in the biological sample to predict responsiveness of the subject to the HDAC inhibitor; and administering to the subject a therapeutically effective amount of a therapeutic regimen including, for example, one or more histone deacetylase (HDAC) inhibitors where the subject is predicted to be responsive to the HDAC inhibitor. The biological sample may be predicted to be responsive to the HDAC inhibitor where expression of the one or more miRNAs in the biological sample and/or c-myc and/or c-myc amplification is elevated as compared to the control sample or is greater than the threshold. Alternatively, the biological sample may be predicted to not be responsive to the HDAC inhibitor where expression of the one or more miRNAs and/or c-myc and/or c-myc amplification in the biological sample is reduced as compared to the control sample or is less than the threshold. The threshold may be set at a level of miRNA and/or c-myc expression and/or c-myc amplification above which a subject is known to respond to treatment with the HDAC inhibitor and below which a subject is known to not respond to treatment with the HDAC inhibitor. In some embodiments, the threshold is set at a level of miRNA and/or c-myc expression and/or c-myc amplification above which 50%, 60%, 70%, 80%, 90%, or 95% of subject(s) respond to treatment with the HDAC inhibitor. In some embodiments, the threshold is set at a level of miRNA and/or c- myc expression and/or c-myc amplification below which 50%, 60%, 70%, 80%, 90%, or 95% of subject(s) do not respond to treatment with the HDAC inhibitor.

[00345] The present disclosure also provides methods for selecting subjects for a clinical trial that are responsive to treatment with a histone deacetylase (HDAC) inhibitor by obtaining a biological sample from the subjects; assaying the biological sample for expression of one or more miRNAs (e.g., one or more of miR-17, miR-20a, miR18a, miR19a, miR-19b or miR92a; or their homologues) and/or c-myc and/or c-myc amplification (e.g., 3, 4, 5, 6 ,7, 8, 9 or 10 copies of c-myc per cell); determining if expression of the one or more miRNAs and/or c-myc in the cell is elevated or reduced compared to a control sample or above or below a threshold; determining if c-myc is amplified in the biological sample as compared to a control sample or above or below a threshold; employing the determination of the expression of the one or more miRNAs and/or c-myc and/or c-myc amplification in the biological sample to predict responsiveness of the subject to the HDAC inhibitor; and selecting subjects for inclusion in a clinical trial that are responsive to the HDAC inhibitor. The biological sample may be predicted to be responsive to the H DAC inhibitor where expression of the one or more miRNAs and/or c-myc and/or c-myc amplification in the biological sample is elevated as compared to the control sample or is greater than the threshold. Alternatively, the biological sample may be predicted to not be responsive to the HDAC inhibitor where expression of the one or more miRNAs and/or c-myc and/or c-myc amplification in the biological sample is reduced as compared to the control sample or is less than the threshold. The threshold may be set at a level of miRNA and/or c-myc expression and/or c-myc amplification above which a subject is known to respond to treatment with the HDAC inhibitor and below which a subject is known to not respond to treatment with the HDAC inhibitor. In some embodiments, the threshold is set at a level of miRNA and/or c-myc expression and/or c-myc amplification above which 50%, 60%, 70%, 80%, 90%, or 95% of subject(s) respond to treatment with the HDAC inhibitor. In some embodiments, the threshold is set at a level of miRNA and/or c-myc expression and/or c-myc amplification below which 50%, 60%, 70%, 80%, 90%, or 95% of subject(s) do not respond to treatment with the HDAC inhibitor.

[00346] The present disclosure also provides methods for screening a test cell for sensitivity to treatment with a histone deacetylase (HDAC) inhibitor by obtaining a test cell; assaying the biological sample for expression of one or more miRNAs (e.g., one or more of miR-17, miR-20a, miR18a, miR19a, miR-19b or miR92a; or their homologues) and/or c-myc and/or a c-myc amplification (e.g., 3, 4, 5, 6 ,7, 8, 9 or 10 copies of c-myc per cell); determining if expression of the one or more miRNAs and/or c-myc in the cell is elevated or reduced compared to a control sample or above or below a threshold; and determining if c- myc is amplified in the biological sample as compared to a control sample or above or below a threshold, wherein the test cell is determined to be sensitive to the HDAC inhibitor where expression of the one or more miRNAs and/or c-myc and/or c-myc amplification in the test cell is elevated as compared to expression of the one or more miRNAs and/or c-myc and/or c-myc amplification in the control cell or is above the threshold and wherein the test cell is determined to not be sensitive to the HDAC inhibitor where expression of the one or more miRNAs and/or c-myc and/or c-myc amplification in the test cell is reduced as compared to expression of the one or more miRNAs and/or c-myc and/or c-myc amplification in the control cell or is less than the threshold. The test cell may be predicted to be sensitive to the HDAC inhibitor where expression of the one or more miRNAs and/or c-myc and/or c-myc amplification in the test cell is elevated as compared to expression of the one or more miRNAs and/or c-myc and/or c-myc amplification in the control cell or is above the threshold. Alternatively, the test cell may be predicted to not be sensitive to the HDAC inhibitor where expression of the one or more miRNAs and/or c-myc and/or c-myc amplification in the test cell is reduced as compared to expression of the one or more miRNAs and/or c-myc and/or c-myc amplification in the control cell or is less than the threshold. The threshold may be set at a level of miRNA and/or c-myc expression and/or c-myc amplification above which a cell is known to be sensitive to treatment with the HDAC inhibitor and below which a cell is known to not be sensitive to treatment with the HDAC inhibitor. In some embodiments, the threshold may be set at a level of miRNA and/or c-myc expression and/or c-myc amplification above which 50%, 60%, 70%, 80%, 90%, or 95% of cells respond to treatment with a HDAC and/or at a level of miRNA and/or c-myc expression and/or c-myc amplification below which 50%, 60%, 70%, 80%, 90%, or 95% of cells do not respond to treatment with a HDAC inhibitor.

[00347] A cell or biological sample may be considered responsive/sensitive to a HDAC inhibitor if the HDAC inhibitor induces apoptosis, decreases cell proliferation, or induces an immune response against the cell and/or biological sample. Responsiveness of a cell or biological sample to a chemotherapeutic agent may also be measured as a reduction in size of the cell or biological sample.

[00348] A subject including, for example, a human patient, may be considered responsive/sensitive to a HDAC inhibitor if the HDAC inhibitor induces apoptosis, decreases cell proliferation, or induces an immune response against a cell and/or biological sample obtained from the subject or patient. Responsiveness of the subject to a chemotherapeutic agent may also be measured as a reduction in size of the cell or biological sample.

[00349] A "histone deacetylase inhibitor" may refer to a compound that binds to an active site of histone deacetylase competitively with a substrate, or a compound having an action to bind with a site different from the active site of histone deacetylase to change the enzyme activity of the histone deacetylase, and includes compounds whose use as a histone deacetylase inhibitor is known, all compounds (synthetic and natural) whose histone deacetylase inhibitory activity has been reported and all the compounds that will be reported in the future. For example, a histone deacetylase inhibitor may include tricostatin A, sodium butyrate, suberoylanilide hydroxamic acid (SAHA), MS-275, Cyclic hydroxamic-acid- containing peptide, Apicidin, and Trapoxin.

[00350] In a preferred embodiment, the HDAC inhibitor is vorinostat (SAHA), MS- 275 or LAQ284.

[00351] A test cell may include a tumor cell and preferably has a histone deacetlyase. For examination of a long-term treatment effect, or effectiveness for individual patients, namely, tailor made medicine, it is possible to culture a cancer cell that can be obtained from a tumor of patient and use the cancer cell as a test cell.

[00352] In some embodiments, "treating" or "treatment" of a disease, disorder, or condition includes at least partially: (1 ) preventing the disease, disorder, or condition, i.e. causing the clinical symptoms of the disease, disorder, or condition not to develop in a mammal that is exposed to or predisposed to the disease, disorder, or condition but does not yet experience or display symptoms of the disease, disorder, or condition; (2) inhibiting the disease, disorder, or condition, i.e., arresting or reducing the development of the disease, disorder, or condition or its clinical symptoms; or (3) relieving the disease, disorder, or condition, i.e., causing regression of the disease, disorder, or condition or its clinical symptoms.

[00353] The term "treatment of cancer" refers to administration to a mammal afflicted with a cancerous condition and refers to an effect that alleviates the cancerous condition by killing the cancerous cells, but also to an effect that results in the inhibition of growth and/or metastasis of the cancer. [00354] An "effective amount," as used herein, refers to the amount of an active composition that is required to confer a therapeutic effect on the subject. A "therapeutically effective amount," as used herein, refers to a sufficient amount of an agent or a compound being administered which will relieve to some extent one or more of the symptoms of the disease, disorder, or condition being treated. In some embodiments, the result is a reduction and/or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system. For example, in some embodiments, an "effective amount" for therapeutic uses is the amount of the composition including a compound as disclosed herein required to provide a clinically significant decrease in disease symptoms without undue adverse side effects. In some embodiments, an appropriate "effective amount" in any individual case is determined using techniques, such as a dose escalation study. The term "therapeutically effective amount" includes, for example, a prophylactically effective amount. In other embodiments, an "effective amount" of a compound disclosed herein, such as a compound of Formula (A) or Formula (I), is an amount effective to achieve a desired pharmacologic effect or therapeutic improvement without undue adverse side effects. In other embodiments, it is understood that "an effect amount" or "a therapeutically effective amount" varies from subject to subject, due to variation in metabolism, age, weight, general condition of the subject, the condition being treated, the severity of the condition being treated, and the judgment of the prescribing physician.

[00355] By the term "chemotherapeutic agent" is meant especially any chemotherapeutic agent other than a histone deacetylase inhibitor ("HDAI") or a derivative thereof. It includes but is not limited to, i. an aromatase inhibitor, ii. an antiestrogen, an anti- androgen (especially in the case of prostate cancer) or a gonadorelin agonist, iii. a topoisomerase I inhibitor or a topoisomerase 1 1 inhibitor, iv. a microtubule active agent, an alkylating agent, an antineoplastic antimetabolite or a platin compound, v. a compound targeting/decreasing a protein or lipid kinase activity or a protein or lipid phosphatase activity, a further anti-angiogenic compound or a compound which induces cell differentiation processes, vi. a bradykinin 1 receptor or an angiotensin 1 1 antagonist, vii. a cyclooxygenase inhibitor, a bisphosphonate, a rapamycin derivative such as everolimus, a heparanase inhibitor (prevents heparan sulphate degradation), e.g. PI 88, a biological response modifier, preferably a lymphokine or interferons, e.g. interferon if, an ubiquitination inhibitor, or an inhibitor which blocks anti-apoptotic pathways, viii. an inhibitor of Ras oncogenic isoforms, e. g. H-Ras, K-Ras or N-Ras, or a farnesyl transferase inhibitor, e.g. L-744, 832 or DK8G557, ix. a telomerase inhibitor, e.g. telomestatin, x. a protease inhibitor, a matrix metalloproteinase inhibitor, a methionine aminopeptidase inhibitor, e.g. bengamide or a derivative thereof, or a proteosome inhibitor, e.g. PS 341. [00356] MiR-17, miR-20a, miR18a, miR19a, miR-19b or miR92a may comprise the nucleotide sequence as set forth in SEQ ID NO: 1 , 2, 3, 4, 5 and 6, respectively. Alternatively, MiR-17, miR-20a, miR18a, miR19a, miR-19b or miR92a may be a variant including, for example, a biologically active variant, of the nucleotide sequence as set forth in SEQ ID NO: 1 , 2, 3, 4, 5 and 6, respectively. C-myc may comprise the amino acid sequence as set forth in SEQ ID NO: 7. Alternatively, c-myc may be a variant including, for example, a biologically active variant, of the amino acid sequence as set forth in SEQ ID NO: 7.

[00357] Guidance in determining which nucleotides or amino acid residues can be substituted, inserted, or deleted without abolishing biological or immunological activity can be found using computer programs well known in the art, such as DNASTAR software. Preferably, amino acid changes in protein variants are conservative amino acid changes, i.e., substitutions of similarly charged or uncharged amino acids. A conservative amino acid change involves substitution of one of a family of amino acids which are related in their side chains. Naturally occurring amino acids are generally divided into four families: acidic (aspartate, glutamate), basic (lysine, arginine, histidine), non-polar (alanine, valine, leucine, isoleucine, proline, phenylalanine, methionine, tryptophan), and uncharged polar (glycine, asparagine, glutamine, cystine, serine, threonine, tyrosine) amino acids. Phenylalanine, tryptophan, and tyrosine are sometimes classified jointly as aromatic amino acids.

[00358] Protein variants include glycosylated forms, aggregative conjugates with other molecules, and covalent conjugates with unrelated chemical moieties. Also, protein variants also include allelic variants, species variants, and muteins. Truncations or deletions of regions which do not affect the differential expression of the gene are also variants. Covalent variants can be prepared by linking functionalities to groups which are found in the amino acid chain or at the N- or C-terminal residue, as is known in the art.

[00359] It will be recognized in the art that some amino acid sequence of c-myc can be varied without significant effect on the structure or function of the protein. If such differences in sequence are contemplated, it should be remembered that there are critical areas on the protein which determine activity. In general, it is possible to replace residues that form the tertiary structure, provided that residues performing a similar function are used. In other instances, the type of residue may be completely unimportant if the alteration occurs at a non-critical region of the protein. The replacement of amino acids can also change the selectivity of binding to cell surface receptors. Thus, the polypeptides of the present invention may include one or more amino acid substitutions, deletions or additions, either from natural mutations or human manipulation.

[00360] Amino acids in the polypeptides of the present invention that are essential for function can be identified by methods known in the art, such as site-directed mutagenesis or alanine-scanning mutagenesis (Cunningham and Wells, Science 244: 1081 -1085 (1989)). The latter procedure introduces single alanine mutations at every residue in the molecule. The resulting mutant molecules are then tested for biological activity such as binding to a natural or synthetic binding partner. Sites that are critical for ligand-receptor binding can also be determined by structural analysis such as crystallization, nuclear magnetic resonance or photoaffinity labeling (Smith, et al., J. Mol. Biol. 224:899-904 (1992) and de Vos, et al. Science 255:306-312 (1992)).

[00361] Variants of MiR-17, miR-20a, miR18a, miR19a, miR-19b or miR92a may include a polynucleotide possessing a nucleotide sequence that possess at least 90% sequence identity, more preferably at least 91 % sequence identity, even more preferably at least 92% sequence identity, still more preferably at least 93% sequence identity, still more preferably at least 94% sequence identity, even more preferably at least 95% sequence identity, still more preferably at least 96% sequence identity, even more preferably at least 97% sequence identity, still more preferably at least 98% sequence identity, and most preferably at least 99% sequence identity, to MiR-17, miR-20a, miR18a, miR19a, miR-19b or miR92a. Variants of c-myc may include a polypeptide possessing an amino acid sequence that possess at least 90% sequence identity, more preferably at least 91 % sequence identity, even more preferably at least 92% sequence identity, still more preferably at least 93% sequence identity, still more preferably at least 94% sequence identity, even more preferably at least 95% sequence identity, still more preferably at least 96% sequence identity, even more preferably at least 97% sequence identity, still more preferably at least 98% sequence identity, and most preferably at least 99% sequence identity, to c-myc. Preferably, this variant may possess at least one biological property in common with the native protein.

[00362] Sequence identity or percent identity is intended to mean the percentage of the same residues shared between two sequences, when the two sequences are aligned using the Clustal method [Higgins et al, Cabios 8:189-191 (1992)] of multiple sequence alignment in the Lasergene biocomputing software (DNASTAR, INC, Madison, Wis.). In this method, multiple alignments are carried out in a progressive manner, in which larger and larger alignment groups are assembled using similarity scores calculated from a series of pairwise alignments. Optimal sequence alignments are obtained by finding the maximum alignment score, which is the average of all scores between the separate residues in the alignment, determined from a residue weight table representing the probability of a given amino acid change occurring in two related proteins over a given evolutionary interval. Penalties for opening and lengthening gaps in the alignment contribute to the score. The default parameters used with this program are as follows: gap penalty for multiple alignments 0; gap length penalty for multiple alignments 0; k-tuple value in pairwise alignments ; gap penalty in pairwise alignment=3; window value in pairwise alignment=5; diagonals saved in pairwise alignment=5. The residue weight table used for the alignment program is PAM250 [Dayhoff, et al., in Atlas of Protein Sequence and Structure, Dayhoff, Ed., NDRF, Washington, Vol. 5, suppl. 3, p. 345, (1978)].

[00363] In one embodiment, the disease or disorder may be cancer. In one embodiment the cancer may be selected from the group consisting of: oral cancer, prostate cancer, rectal cancer, non-small cell lung cancer, lip and oral cavity cancer, liver cancer, lung cancer, anal cancer, kidney cancer, vulvar cancer, breast cancer, oropharyngeal cancer, nasal cavity and paranasal sinus cancer, nasopharyngeal cancer, urethra cancer, small intestine cancer, bile duct cancer, bladder cancer, ovarian cancer, laryngeal cancer, hypopharyngeal cancer, gallbladder cancer, colon cancer, colorectal cancer, head and neck cancer, glioma; parathyroid cancer, penile cancer, vaginal cancer, thyroid cancer, pancreatic cancer, esophageal cancer, Hodgkin's lymphoma, leukemia-related disorders, mycosis fungoides, and myelodysplastic syndrome.

[00364] In another embodiment the cancer may be non-small cell lung cancer, pancreatic cancer, breast cancer, ovarian cancer, colorectal cancer, or head and neck cancer. In yet another embodiment the cancer may be a carcinoma, a tumor, a neoplasm, a lymphoma, a melanoma, a glioma, a sarcoma, or a blastoma.

[00365] In one embodiment the carcinoma may be selected from the group consisting of: carcinoma, adenocarcinoma, adenoid cystic carcinoma, adenosquamous carcinoma, adrenocortical carcinoma, well differentiated carcinoma, squamous cell carcinoma, serous carcinoma, small cell carcinoma, invasive squamous cell carcinoma, large cell carcinoma, islet cell carcinoma, oat cell carcinoma, squamous carcinoma, undifferentiatied carcinoma, verrucous carcinoma, renal cell carcinoma, papillary serous adenocarcinoma, merkel cell carcinoma, hepatocellular carcinoma, soft tissue carcinomas, bronchial gland carcinomas, capillary carcinoma, bartholin gland carcinoma, basal cell carcinoma, carcinosarcoma, papilloma/carcinoma, clear cell carcinoma, endometrioid adenocarcinoma, mesothelial, metastatic carcinoma, mucoepidermoid carcinoma, cholangiocarcinoma, actinic keratoses, cystadenoma, and hepatic adenomatosis.

[00366] In another embodiment the tumor may be selected from the group consisting of: astrocytic tumors, malignant mesothelial tumors, ovarian germ cell tumors, supratentorial primitive neuroectodermal tumors, Wilms tumors, pituitary tumors, extragonadal germ cell tumors, gastrinoma, germ cell tumors, gestational trophoblastic tumors, brain tumors, pineal and supratentorial primitive neuroectodermal tumors, pituitary tumors, somatostatin-secreting tumors, endodermal sinus tumors, carcinoids, central cerebral astrocytoma, glucagonoma, hepatic adenoma, insulinoma, medulloepithelioma, plasmacytoma, vipoma, and pheochromocytoma.

[00367] In yet another embodiment the neoplasm may be selected from the group consisting of: intraepithelial neoplasia, multiple myeloma/plasma cell neoplasm, plasma cell neoplasm, interepithelial squamous cell neoplasia, endometrial hyperplasia, focal nodular hyperplasia, hemangioendothelioma, and malignant thymoma. In a further embodiment the lymphoma may be selected from the group consisting of: nervous system lymphoma, AIDS- related lymphoma, cutaneous T-cell lymphoma, non-Hodgkin's lymphoma, lymphoma, and Waldenstrom's macroglobulinemia. In another embodiment the melanoma may be selected from the group consisting of: acral lentiginous melanoma, superficial spreading melanoma, uveal melanoma, lentigo maligna melanomas, melanoma, intraocular melanoma, adenocarcinoma nodular melanoma, and hemangioma. In yet another embodiment the sarcoma may be selected from the group consisting of: adenomas, adenosarcoma, chondosarcoma, endometrial stromal sarcoma, Ewing's sarcoma, Kaposi's sarcoma, leiomyosarcoma, rhabdomyosarcoma, sarcoma, uterine sarcoma, osteosarcoma, and pseudosarcoma. In one embodiment the glioma may be selected from the group consisting of: glioma, brain stem glioma, and hypothalamic and visual pathway glioma. In another embodiment the blastoma may be selected from the group consisting of: pulmonary blastoma, pleuropulmonary blastoma, retinoblastoma, neuroblastoma, medulloblastoma, glioblastoma, and hemangiblastomas.

[00368] A therapeutic regimen as referred to herein may comprises the use of an HDACi and one or more further chemotherapeutic agents. Optionally, the therapeutic regimen may also include additional therapeutic, non-therapeutic or chemotherapeutic agents as described herein. Suitable therapeutic agents include antibodies, such as Avastin, Erbitux and Herceptin, and other therapeutic compounds, such as Tarceva and Tykerb.

[00369] In a preferred embodiment, a therapeutic treatment regimen comprises the use of one or more HDACI, one or more further chemotherapeutic agents, and one or more therapeutic antibodies and/or therapeutic compounds.

[00370] Biological samples or test cells that may be used in the methods of the present disclosure may include tissues, cells, biological fluids and isolates thereof, isolated from a subject, as well as tissues, cells and fluids present within a subject {e.g., a patient). Preferably, biological samples comprise cells, most preferably tumor cells, that are isolated from body samples, such as, but not limited to, smears, sputum, biopsies, secretions, cerebrospinal fluid, bile, blood, serum, lymph fluid, urine and faeces, or tissue which has been removed from organs, such as breast, lung, intestine, skin, cervix, prostate, and stomach. Biological samples may also include sections of tissues such as frozen sections taken for histological purposes.

HDAC and HDAC Inhibitors

[00371] In eukaryotic cells, genomic DNA in chromatin associates with histones to form nucleosomes. Each nucleosome consists of a protein octamer made up of two copies of each of histones H2A, H2B, H3 and H4. DNA winds around this protein core, with the basic amino acids of the histones interacting with the negatively charged phosphate groups of the DNA. The most common posttranslational modification of these core histones is the reversible acetylation of the £-amino groups of conserved, highly basic N-terminal lysine residues. Reversible acetylation of histones is a major regulator of gene expression that acts by altering accessibility of transcription factors to DNA. In normal cells, histone deacetylases (HDAC) and histone acetyltransferases (HAT) together control the level of acetylation of histones to maintain a balance. Inhibition of HDAC results in the accumulation of hyperacetylated histones, which results in a variety of cellular responses.

[00372] Histone acetylation and deacetylation has long been linked to transcriptional control. In some embodiments, HDAC inhibitors, including trichostatin A, sodium butyrate, suberoylanilide hydroxamic acid (SAHA), depsipeptide, MS-275, and aphicidin, among others, promote histone acetylation, resulting in relaxation of the chromatin structure. Chromatin relaxation and uncoiling permits and enhances the expression of diverse genes, including those involved in the differentiation process, e.g. p21 clpl . In fact, HDIs, e.g. SAHA, sodium butyrate, have been shown to induce maturation in various human leukemia cell lines.

[00373] Mammalian HDACs are divided into three major classes based on their structural or sequence homologies to the three distinct yeast HDACs: Rpd3 (class I), Hdal (class II), and Sir2/Hst (class III). The Rpd3 homologous class I includes HDACs 1 , 2, 3, 8, and 1 1 ; the Hdal homologous class II includes HDACs 4, 5, 6, 7, 9 (9a and 9b), and 10; the Sir2/Hst homologous class III SIR Tl , 2, 3, 4, 5, 6, and 7. Recent studies revealed an additional family of cellular factors that possesses intrinsic HAT or HDAC activities. These appear to be non- histone proteins that participate in regulation of the cell cycle, DNA repair, and transcription. A number of transcriptional coactivators, including but not limited to p400AF, BRCA2, and ATM-like proteins, function as HATs. Some transcriptional repressors exhibit HDAC activities in the context of chromatin by recruiting a common chromatin- modifying complex. For instance, the Mas protein family (Masl, Mxil, Mad3, and Mad4) comprises a basic-helix-loop-helix-loop-helix-zipper class of transcriptional factors that heterodimerize with Max at their DNA binding sites. Mad:Max heterodimers act as transcriptional repressors at their DNA binding sites through recruitment of "repressor complexes." Mutations that prevent interaction with either Max or the msin3 co-repressor complex fail to arrest cell growth. Accordingly, HDAC inhibitor used herein refers to any agent capable of inhibiting the HDAC activity from any of the proteins described above.

[00374] Preferred classes of HDAC inhibitors include those as listed in Table 1 below:

Table 1 : HDACI Classes

[00375] The terms "histone deacetylase" and "HDAC" may refer to any one of a family of enzymes that remove acetyl groups from the -amino groups of lysine residues at the N-terminus of a histone. Unless otherwise indicated by context, the term "histone" is meant to refer to any histone protein, including H1 , H2A, H2B, H3, H4, and H5, from any species. Human HDAC proteins or gene products, include, but are not limited to, HDAC-I, HDAC-2, HDAC-3, HDAC4, HDAC-5, HDAC-6, HDAC-7, HDAC-8, HDAC-9, HDAC-10, and HDAC-1 1. In some embodiments, the HDAC is also derived from a protozoal or fungal source.

[00376] Inhibitors of HDAC have been studied for their therapeutic effects on cancer cells. For example, butyric acid and its derivatives, including sodium phenylbutyrate, have been reported to induce apoptosis in vitro in human colon carcinoma, leukemia and retinoblastoma cell lines. However, butyric acid and its derivatives are not useful pharmacological agents because they tend to be metabolized rapidly and have a very short half-life in vivo. Other inhibitors of HDAC that have been widely studied for their anti-cancer activities are trichostatin A and trapoxin.

[00377] The terms "histone deacetylase inhibitor," "inhibitor of histone deacetylase," "HDAC inhibitor," and "inhibitor of HDAC" are used interchangeably to identify a compound, which is capable of interacting with a HDAC and inhibiting its activity, more particularly its enzymatic activity. Inhibiting HDAC enzymatic activity means reducing the ability of a HDAC to remove an acetyl group from a histone. In some embodiments, such inhibition is specific, i.e. the HDAC inhibitor reduces the ability of a HDAC to remove an acetyl group from a histone at a concentration that is lower than the concentration of the inhibitor that is required to produce some other, unrelated biological effect.

[00378] HDAC inhibitors include, but not limited to, (1 ) short-chain fatty acids for example butyrate, 4- phenylbutyrate or valproic acid; (2) hydroxamic acids for example suberoylanilide hydroxamic acid (SAHA), biaryl hydroxamate A-161906, bicyclic aryl-N- hydroxycarboxamides, CG-1 52 1 , PXD-101 , sulfonamide hydroxamic acid, LAQ-824, oxamflatin, scriptaid, m-carboxy cinnamic acid bishydroxamic acid, trapoxin- hydroxamic acid analogue, trichostatins like trichostatin A (TSA), m-carboxycinnamic acid bis- hydroxamideoxamflatin (CBHA), ABHA, Scriptaid, pyroxamide, and propenamides; (3) epoxyketone- containing cyclic tetrapeptides for example trapoxins, apidicin, depsipeptide, HC-toxin, chlamydocin, diheteropeptin, WF-3 161 , Cyl-I and Cyl-2; (4) benzamides or non- epoxyketone-containing cyclic tetrapeptides for example FR901228; apicidin, cyclic- hydroxamic-acid-containing peptides (CHAPs), benzamides, MS-275 (MS-27-275), and Cl- 994; (5) depudecin; (6) PXDIOI; and (7) organosulfur compounds. Additional examples of HDAC inhibitors include TSA, TPXA and B, oxamflatin, FR901 228 (FK228), trapoxin B, CHAPI, aroyl- pyrrolylhydroxy-amides (APHAs), apicidin, and depudecin.

[00379] In some embodiments, the HDAC inhibitor is a reversible inhibitor and is administered for a period prior to and/or during the administration of radiation and/or chemotherapy, and optionally continuing for a period after radiation and/or chemotherapy. In some embodiments, the HDAC inhibitor is chosen from among the compounds selected from the group consisting of trichostatin A, FR, M344, SAHA, combinations thereof, and the like. Methods for determining HDAC activity in vivo or in vitro are known.

[00380] In some embodiments, HDAC inhibitors are used in combination therapy with chemical agents that are understood to mimic the effects of radiotherapy and/or that function by direct contact with DNA, such as, for example, DNA alkylating agents. In some embodiments, agents for use in combination with HDAC inhibitors in methods provided include cisplatinum, adriamycin (Doxirubicin), topoisomerase inhibitors (Etoposide), 5-FU, and taxol.

[00381] According to this aspect, HDAC inhibitors are used synergistically at effective amounts that result in concentrations in the fluid of a target tissue that are less than about twice the IC50 concentration for the particular compound. In some embodiments, the effective amount is about equal to the IC50 concentration. In another embodiment, the HDAC inhibitors are administered at lower amounts such as about 50% of the IC50 concentration, or less, at the target tissue. Furthermore, in other embodiments, the HDAC inhibitor is administered locally so that the concentration at the target tissue is in the effective range and lower elsewhere.

[00382] In some other embodiments, any inhibitor of HDAC that provides a synergistic effect in combination with radiotherapy or chemotherapy is used in accordance with the methods described herein, provided that the inhibitor has acceptably low toxicity to the host.

[00383] In some embodiments, the following are desired characteristics of the HDAC inhibitory synergistic agent: high inhibitory activity at low concentrations (such as having an IC50 of less than about 800 ng/ml, about 320 ng/ml or less, or about 60 ng/ml or less, i.e. about 5 ng/ml), reversible HDAC inhibition, low toxicity at synergistic doses, rapid clearance following termination of administration. An acceptable combination of these characteristics includes compromises in one or more categories.

[00384] Biological samples that may be used in the methods of the present disclosure may include tissues, cells, biological fluids and isolates thereof, isolated from a subject, as well as tissues, cells and fluids present within a subject {e.g., a patient). Preferably, biological samples comprise cells, most preferably tumor cells, that are isolated from body samples, such as, but not limited to, smears, sputum, biopsies, secretions, cerebrospinal fluid, bile, blood, lymph fluid, urine and faeces, or tissue which has been removed from organs, such as breast, lung, intestine, skin, cervix, prostate, and stomach. Biological samples may also include sections of tissues such as frozen sections taken for histological purposes.

[00385] MiRNA including, MiR-17, MiR-18A, Mir18B, Mir19A, Mir19B1 , Mir19B2, Mir20A, Mir92A1 , Mir92A2, Mir106A, Mir20B, and/or c-myc may be detected in one or more cells in a biological sample or may be detected in a field (e.g., a microscopic field) of a biological sample, for example, in methods involving FISH or in-situ hybridization.

Detection and/or Quantitation of MiRNA and/or C-myc Expression and/or C-Myc Amplification

[00386] A number of methodologies may be employed to analyze including, detect and/or quantitate the expression (i.e., expression level or amount) of miRNA expression (e.g., one or more of miR-17, miR-20a, miR18a, miR19a, miR-19b or miR92a) and/or c-myc expression and/or the presence of a c-myc amplification in a cell and/or a biological sample. Such expression and/or amplification may be detected at the protein level and/or nucleic acid level. Those skilled in the art will appreciate that the methods indicated below represent some of the preferred ways in which the expression of miRNA and/or c-myc and/or the presence of a c-myc amplification may be detected and/or quantitated and in no manner limit the scope of methodologies that may be employed. Those skilled in the art will also be able to determine operative and optimal assay conditions for each determination by employing routine experimentation. Such methods may include but are not limited to in situ hybridization (ISH), Western blots, ELISA, immunoprecipitation, immunofluorescence, flow cytometry, northern blots, PCR, and immunocytochemistry (IHC). MiR-17, MiR-18A, Mir18B, Mir19A, Mir19B1 , Mir19B2, Mir20A, Mir92A1 , Mir92A2, Mir106A or Mir20B may comprise the nucleotide sequences as set forth in SEQ ID NOS: 1 -1 1 , respectively. Alternatively, MiR-17, MiR-18A, Mir18B, Mir19A, Mir19B1 , Mir19B2, Mir20A, Mir92A1 , Mir92A2, Mir106A or Mir20B may be a variant of the nucleotide sequence as set forth in SEQ ID NOS: 1 -1 1 , respectively. Additionally, c-myc may comprise the polypeptide sequence as set forth in SEQ ID NO: 12 or may be a variant of SEQ ID NO: 12.

[00387] In another embodiment, the methods further involve obtaining a control sample and detecting miRNA and/or c-myc expression and/or the presence of a c-myc amplification in this control sample, such that the presence or absence miRNA and/or c-myc expression and/or the presence of a c-myc amplification in the control sample is determined. A negative control sample is useful if there is an absence of miRNA and/or c-myc expression and/or the absence of c-myc amplification, whereas a positive control sample is useful if there is a presence of miRNA and/or c-myc expression and/or the presence of a c-myc amplification. For the negative control, the sample may be from the same individual as the test sample (i.e. different location such as tumor versus non-tumor) or may be from a different individual known to have an absence of miRNA and/or c-myc expression and/or the absence of a c-myc amplification.

Detection of c-myc Amplification

[00388] The present invention encompasses methods of gene amplification known to those of skill in the art, see, for example, Boxer, J. Clin. Pathol. 53: 19-21 (2000). Such techniques include in situ hybridization (Stoler, Clin. Lab. Med. 12:215-36 (1990), using radioisotope or fluorophore-labeled probes; polymerase chain reaction (PCR); quantitative Southern blotting, dot blotting and other techniques for quantitating individual genes. Preferably, probes or primers selected for gene amplification evaluation are highly specific, to avoid detecting closely related homologous genes. Alternatively, antibodies may be employed that can recognize specific duplexes, including DNA duplexes, RNA duplexes, and DNA-RNA hybrid duplexes or DNA-protein duplexes. The antibodies in turn may be labeled and the assay may be carried out where the duplex is bound to a surface, so that upon the formation of duplex on the surface, the presence of antibody bound to the duplex can be detected.

[00389] In one embodiment, the biological sample contains nucleic acids from the test subject. The nucleic acids may be mRNA or genomic DNA molecules from the test subject.

1. Amplification Based Assays

[00390] In one embodiment of the present invention, amplification-based assays can be used to measure copy number of the c-myc gene. In such amplification-based assays, the corresponding c-myc nucleic acid sequence acts as a template in an amplification reaction (for example, Polymerase Chain Reaction or PCR). In a quantitative amplification, the amount of amplification product will be proportional to the amount of template in the original sample. Comparison to appropriate controls provides a measure of the copy-number of the c-myc gene, corresponding to the specific probe used. The presence of a higher level of amplification product, as compared to a control, is indicative of amplified c-myc.

a. Quantitative PCR

[00391] Methods of "quantitative" amplification are well known to those of skill in the art. For example, quantitative PCR involves simultaneously co-amplifying a known quantity of a control sequence using the same primers. This provides an internal standard that may be used to calibrate the PCR reaction. Detailed protocols for quantitative PCR are provided, for example, in Innis et al. (1990) PCR Protocols, A Guide to Methods and Applications, Academic Press, Inc. N.Y. The known nucleic acid sequence for the Met (Accession No.: NM 000245) is sufficient to enable one of skill to routinely select primers to amplify any portion of the c-myc gene.

b. Real Time PCR

[00392] Real time PCR is another amplification technique that can be used to determine gene copy levels or levels of c-myc mRNA expression. (See, e.g., Gibson et al., Genome Research 6:995-1001 , 1996; Heid et al., Genome Research 6:986-994, 1996). Real-time PCR evaluates the level of PCR product accumulation during amplification. This technique permits quantitative evaluation of mRNA levels in multiple samples. For gene copy levels, total genomic DNA is isolated from a sample. For mRNA levels, mRNA is extracted from tumor and normal tissue and cDNA is prepared using standard techniques. Real-time PCR can be performed, for example, using a Perkin Elmer/Applied Biosystems (Foster City, Calif.) 7700 Prism instrument. Matching primers and fluorescent probes can be designed for genes of interest using, for example, the primer express program provided by Perkin Elmer/Applied Biosystems (Foster City, Calif.)- Optimal concentrations of primers and probes can be initially determined by those of ordinary skill in the art, and control (for example, beta-actin) primers and probes may be obtained commercially from, for example, Perkin Elmer/Applied Biosystems (Foster City, Calif.). To quantitate the amount of the specific nucleic acid of interest in a sample, a standard curve is generated using a control. Standard curves may be generated using the Ct values determined in the real-time PCR, which are related to the initial concentration of the nucleic acid of interest used in the assay. Standard dilutions ranging from 10-10⁶ copies of the gene of interest are generally sufficient. In addition, a standard curve is generated for the control sequence. This permits standardization of initial content of the nucleic acid of interest in a tissue sample to the amount of control for comparison purposes.

[00393] Methods of real-time quantitative PCR using TaqMan probes are well known in the art. Detailed protocols for real-time quantitative PCR are provided, for example, for RNA in: Gibson et al., 1996, A novel method for real time quantitative RT-PCR. Genome Res., 10:995-1001 ; and for DNA in: Heid et al., 1996, Real time quantitative PCR. Genome Res., 10:986-994.

[00394] A TaqMan-based assay also can be used to quantify MET polynucleotides. TaqMan based assays use a fluorogenic oligonucleotide probe that contains a 5' fluorescent dye and a 3' quenching agent. The probe hybridizes to a PCR product, but cannot itself be extended due to a blocking agent at the 3' end. When the PCR product is amplified in subsequent cycles, the 5' nuclease activity of the polymerase, for example, AmpliTaq, results in the cleavage of the TaqMan probe. This cleavage separates the 5' fluorescent dye and the 3' quenching agent, thereby resulting in an increase in fluorescence as a function of amplification.

c. Other Amplification Methods

[00395] Other suitable amplification methods include, but are not limited to ligase chain reaction (LCR) (see Wu and Wallace (1989) Genomics 4:560, Landegren et al. (1988) Science 241 :1077, and Barringer et al. (1990) Gene 89:1 17), transcription amplification (Kwoh et al. (1989) Proc. Natl. Acad. Sci. USA 86:1 173), self-sustained sequence replication (Guatelli et al. (1990) Proc. Nat. Acad. Sci. USA 87:1874), dot PCR, and linker adapter PCR, etc.

2. Hybridization Based Assays

[00396] Hybridization assays can be used to detect c-myc copy number. Hybridization-based assays include, but are not limited to, traditional "direct probe" methods such as Southern blots or in situ hybridization (e.g., FISH), and "comparative probe" methods such as comparative genomic hybridization (CGH). The methods can be used in a wide variety of formats including, but not limited to substrate— (e.g. membrane or glass) bound methods or array-based approaches as described below.

a. Southern Blot

[00397] One method for evaluating the copy number of c-myc encoding nucleic acid in a sample involves a Southern transfer. Methods for doing Southern Blots are known to those of skill in the art (see Current Protocols in Molecular Biology, Chapter 19, Ausubel, et al., Eds., Greene Publishing and Wiley-lnterscience, New York, 1995, or Sambrook et al., Molecular Cloning: A Laboratory Manual, 2d Ed. vol. 1-3, Cold Spring Harbor Press, NY, 1989). In such an assay, the genomic DNA (typically fragmented and separated on an electrophoretic gel) is hybridized to a probe specific for the target region. Comparison of the intensity of the hybridization signal from the probe for the target region with control probe signal from analysis of normal genomic DNA (e.g., a non-amplified portion of the same or related cell, tissue, organ, etc.) provides an estimate of the relative copy number of the target nucleic acid. An intensity level that is higher than the control is indicative of amplified c-myc.

b. Fluorescence in situ hybridization (FISH)

[00398] In another embodiment, FISH is used to determine the copy number of the c-myc gene in a sample. Fluorescence in situ hybridization (FISH) is known to those of skill in the art (see Angerer, 1987 Meth. Enzymol., 152: 649). Generally, in situ hybridization comprises the following major steps: (1 ) fixation of tissue or biological structure to be analyzed; (2) pre-hybridization treatment of the biological structure to increase accessibility of target DNA, and to reduce nonspecific binding; (3) hybridization of the mixture of nucleic acids to the nucleic acid in the biological structure or tissue; (4) post-hybridization washes to remove nucleic acid fragments not bound in the hybridization, and (5) detection of the hybridized nucleic acid fragments.

[00399] In a typical in situ hybridization assay, cells or tissue sections are fixed to a solid support, typically a glass slide. If a nucleic acid is to be probed, the cells are typically denatured with heat or alkali. The cells are then contacted with a hybridization solution at a moderate temperature to permit annealing of labeled probes specific to the nucleic acid sequence encoding the protein. The targets (e.g., cells) are then typically washed at a predetermined stringency or at an increasing stringency until an appropriate signal to noise ratio is obtained.

[00400] The probes used in such applications are typically labeled, for example, with radioisotopes or fluorescent reporters. Preferred probes are sufficiently long, for example, from about 50, 100, or 200 nucleotides to about 1000 or more nucleotides, to enable specific hybridization with the target nucleic acid(s) under stringent conditions.

[00401] In some applications it is necessary to block the hybridization capacity of repetitive sequences. Thus, in some embodiments, tRNA, human genomic DNA, or Cot-1 DNA is used to block non-specific hybridization. Thus, in one embodiment of the present invention, the presence or absence of c-myc amplification is determined by FISH.

c. Comparative Genomic Hybridization (CGH)

[00402] In comparative genomic hybridization methods, a "test" collection of nucleic acids (e.g. from a possible tumor) is labeled with a first label, while a second collection (e.g. from a normal cell or tissue) is labeled with a second label. The ratio of hybridization of the nucleic acids is determined by the ratio of the first and second labels binding to each fiber in an array. Differences in the ratio of the signals from the two labels, for example, due to gene amplification in the test collection, is detected and the ratio provides a measure of the gene copy number, corresponding to the specific probe used. A cytogenetic representation of DNA copy-number variation can be generated by CGH, which provides fluorescence ratios along the length of chromosomes from differentially labeled test and reference genomic DNAs. In another embodiment of the present invention, comparative genomic hybridization may be used to detect the presence or absence of c-myc amplification.

d. Microarray Based Comparative Genomic Hybridization

[00403] In an alternative embodiment of the present invention, DNA copy numbers are analyzed via microarray-based platforms. Microarray technology offers high resolution. For example, the traditional CGH generally has a 20 Mb limited mapping resolution; whereas in microarray-based CGH, the fluorescence ratios of the differentially labeled test and reference genomic DNAs provide a locus-by-locus measure of DNA copy-number variation, thereby achieving increased mapping resolution. Details of various microarray methods can be found in the literature. See, for example, U.S. Pat. No. 6,232,068; Pollack et al., Nat. Genet., 23(1 ):41-6, (1999), Pastinen (1997) Genome Res. 7: 606-614; Jackson (1996) Nature Biotechnology 14:1685; Chee (1995) Science 274: 610; WO 96/17958, Pinkel et al. (1998) Nature Genetics 20: 207-21 1 and others.

[00404] The DNA used to prepare the arrays of the invention is not critical. For example, the arrays can include genomic DNA, e.g. overlapping clones that provide a high resolution scan of a portion of the genome containing the desired gene, or of the gene itself. Genomic nucleic acids can be obtained from, e.g., HACs, MACs, YACs, BACs, PACs, P1 s, cosmids, plasmids, inter-Alu PCR products of genomic clones, restriction digests of genomic clones, cDNA clones, amplification (e.g., PCR) products, and the like. Arrays can also be produced using oligonucleotide synthesis technology. Thus, for example, U.S. Pat. No. 5, 143,854 and PCT Patent Publication Nos. WO 90/15070 and WO 92/10092 teach the use of light-directed combinatorial synthesis of high density oligonucleotide arrays.

[00405] Hybridization protocols suitable for use with the methods of the invention are described, e.g., in Albertson (1984) EMBO J. 3: 1227-1234; Pinkel (1988) Proc. Natl. Acad. Sci. USA 85: 9138-9142; EPO Pub. No. 430,402; Methods in Molecular Biology, Vol. 33: In situ Hybridization Protocols, Choo, ed., Humana Press, Totowa, N.J. (1994), Pinkel et al. (1998) Nature Genetics 20: 207-21 1 , or of Kallioniemi (1992) Proc. Natl. Acad Sci USA 89:5321 -5325 (1992), etc.

[00406] The sensitivity of the hybridization assays may be enhanced through use of a nucleic acid amplification system that multiplies the target nucleic acid being detected. Examples of such systems include the polymerase chain reaction (PCR) system and the ligase chain reaction (LCR) system. Other methods recently described in the art are the nucleic acid sequence based amplification (NASBAO, Cangene, Mississauga, Ontario) and Q Beta Replicase systems.

[00407] In another embodiment of the present invention, kits useful for the detection of Met amplification are disclosed. Such kits may include any or all of the following: assay reagents, buffers, specific nucleic acids or antibodies (e.g. full-size monoclonal or polyclonal antibodies, single chain antibodies {e.g., scFv), or other gene product binding molecules), and other hybridization probes and/or primers, and/or substrates for polypeptide gene products.

[00408] In addition, the kits may include instructional materials containing directions (i.e., protocols) for the practice of the methods of this invention. While the instructional materials typically comprise written or printed materials they are not limited to such. Any medium capable of storing such instructions and communicating them to an end user is contemplated by this invention. Such media include, but are not limited to electronic storage media (e.g., magnetic discs, tapes, cartridges, chips), optical media (e.g., CD ROM), and the like. Such media may include addresses to internet sites that provide such instructional materials.

Detection of miRNA and/or c-myc Expression

[00409] MiRNA and/or c-myc expression (e.g., expression of one or more of miR- 17, miR-20a, miR18a, miR19a, miR-19b or miR92a and/or c-myc) may be assayed (e.g., determined) by methods which detect particular mRNAs in cells. These include, hybridization assays using complementary DNA probes (such as in situ hybridization using labeled riboprobes, Northern blot and related techniques) and various nucleic acid amplification assays (such as RT-PCR using complementary primers specific for miR-17, miR-20a, miR18a, miR19a, miR-19b or miR92a and/or c-myc, and other amplification type detection methods, such as, for example, branched DNA, SISBA, TMA and the like). Protocols for the detection of specific mRNAs in a sample are well known in the art (Sambrook et al., (1990) Molecular Cloning - A Laboratory Manual, Cold Spring Harbor Laboratory Press; Ausubel et al., (1998) Current Protocols in Molecular Biology, Wiley).

[00410] MiRNAs that may be detected by the methods of the instant disclosure include those referenced in Table 1 below.

Table 1 : MiRNA sequences

92a2 tataaagtat tgcacttgtc ccg gcctgtg gaaga MIR106A hsa-miR- NR_029523 ccttggccat gtaaaagtgc ttacagtgca ggtagctttt 10 106a tgagatctac tgcaatgtaa gcacttctta cattaccatg g

MIR20B has-miR- NR_029950 agtaccaaag tgctcatagt gcaggtagtt ttggcatgac 1 1

20B tctactgtag tatgggcact tccagtact

[0041 1] Detection of the RNA products of the molecular marker genes may be accomplished by a variety of methods. Some methods are quantitative and allow estimation of the original levels of RNA between the cancer and control cells, whereas other methods are merely qualitative. Additional information regarding the methods presented below may be found in Ausubel et al., (2003) Current Protocols in Molecular Biology, John Wiley & Sons, New York, N.Y., or Sambrook et al. (1989) Molecular Cloning: A Laboratory Manual, Cold Spring Harbor Press, Cold Spring Harbor, N.Y. A person skilled in the art will know which parameters may be manipulated to optimize detection of the mRNA of interest.

[00412] Quantitative real-time PCR (QRT-PCR) may be used to measure the differential expression of a molecular marker in a test cell and a control cell. In QRT-PCR, the RNA template is generally reverse transcribed into cDNA, which is then amplified via a PCR reaction. The PCR amplification process is catalyzed by a thermostable DNA polymerase. Non-limiting examples of suitable thermostable DNA polymerases include Taq DNA polymerase, Pfu DNA polymerase, Tli (also known as Vent) DNA polymerase, Tfl DNA polymerase, and Tth DNA polymerase. The PCR process may comprise 3 steps (i.e., denaturation, annealing, and extension) or 2 steps (i.e., denaturation and annealing/extension). The temperature of the annealing or annealing/extension step can and will vary, depending upon the amplification primers. That is, their nucleotide sequences, melting temperatures, and/or concentrations. The temperature of the annealing or annealing/extending step may range from about 50° C. to about 75° C. The amount of PCR product is followed cycle-by-cycle in real time, which allows for determination of the initial concentrations of mRNA. The reaction may be performed in the presence of a dye that binds to double-stranded DNA, such as SYBR Green. The reaction may also be performed with a fluorescent reporter probes, such as TAQMAN® probes (Applied Biosystems, Foster City, Calif.) that fluoresce when the quencher is removed during the PCR extension cycle. Fluorescence values are recorded during each cycle and represent the amount of product amplified to that point in the amplification reaction. The cycle when the fluorescent signal is first recorded as statistically significant is the threshold cycle (Ct). To minimize errors and reduce any sample-to-sample variation, QRT-PCR is typically performed using an internal standard. The ideal internal standard is expressed at a constant level among different tissues, and is unaffected by the experimental treatment. Suitable internal standards include, but are not limited to, mRNAs for the housekeeping genes glyceraldehyde-3- phosphate-dehydrogenase (GAPDH) and beta-actin.

[00413] Reverse-transcriptase PCR (RT-PCR) may also be used to measure the differential expression of a molecular marker. As above, the RNA template is reverse transcribed into cDNA, which is then amplified via a typical PCR reaction. After a set number of cycles the amplified DNA products are typically separated by gel electrophoresis. Comparison of the relative amount of PCR product amplified in the different cells will reveal whether the molecular marker is differentially expressed in the cancer cell.

[00414] Differential expression of a molecular marker may also be measured using a nucleic acid microarray. In this method, single-stranded nucleic acids (e.g., cDNAs, oligonucleotides, etc.) are plated, or arrayed, on a solid support. The solid support may be a material such as glass, silica-based, silicon-based, a synthetic polymer, a biological polymer, a copolymer, a metal, or a membrane. The form or shape of the solid support may vary, depending on the application. Suitable examples include, but are not limited to, slides, strips, plates, wells, microparticles, fibers (such as optical fibers), gels, and combinations thereof. The arrayed immobilized sequences are generally hybridized with specific DNA probes from the cells of interest. Fluorescently labeled cDNA probes may be generated through incorporation of fluorescently labeled deoxynucleotides by reverse transcription of RNA extracted from the cells of interest. The probes are hybridized to the immobilized nucleic acids on the microchip under highly stringent conditions. After stringent washing to remove non-specifically bound probes, the chip is scanned by confocal laser microscopy or by another detection method, such as a CCD camera. Quantitation of hybridization of each arrayed element allows for assessment of corresponding mRNA abundance. With dual color fluorescence, separately labeled cDNA probes generated from two sources of RNA are hybridized pairwise to the array. The relative abundance of the transcripts from the two sources corresponding to each specified molecular marker is thus determined simultaneously. Microarray analysis may be performed by commercially available equipment, following manufacturer's protocols, such as by using the Affymetrix GenChip technology, or Incyte's microarray technology.

[00415] Differential expression of a molecular marker may also be measured using Northern blotting. For this, RNA samples are first separated by size via electrophoresis in an agarose gel under denaturing conditions. The RNA is then transferred to a membrane, crosslinked, and hybridized, under highly stringent conditions, to a labeled DNA probe. After washing to remove the non-specifically bound probe, the hybridized labeled species are detected using techniques well known in the art. The probe may be labeled with a radioactive element, a chemical that fluoresce when exposed to ultraviolet light, a tag that is detected with an antibody, or an enzyme that catalyses the formation of a colored or a fluorescent product. A comparison of the relative amounts of RNA detected in the different cells will reveal whether the expression of the molecular marker is changed in the cancer cell.

[00416] Nuclease protection assays may also be used to monitor the differential expression of a molecular marker in cancer and control cells. In nuclease protection assays, an antisense probe hybridizes in solution to an RNA sample. The antisense probe may be labeled with an isotope, a fluorophore, an enzyme, or another tag. Following hybridization, nucleases are added to degrade the single-stranded, unhybridized probe and RNA. An acrylamide gel is used to separate the remaining protected double-stranded fragments, which are then detected using techniques well known in the art. Again, qualitative differences in expression may be detected.

[00417] Differential expression of a molecular marker may also be measured using in situ hybridization. This type of hybridization uses a labeled antisense probe to localize a particular mRNA in cells of a tissue section. The hybridization and washing steps are generally performed under highly stringent conditions. The probe may be labeled with a fluorophore or a small tag (such as biotin or digoxigenin) that may be detected by another protein or antibody, such that the labeled hybrid may be visualized under a microscope. The transcripts of a molecular marker may be localized to the nucleus, the cytoplasm, or the plasma membrane of a cell.

[00418] Expression of the molecular marker or markers will generally be measured in a cancer cell relative to a control cell. The cell may be isolated from a subject so that expression of the marker may be examined in vitro. The type of biopsy used to isolated cells can and will vary, depending upon the location and nature of the cancer.

[00419] A sample of cells, tissue, or fluid may be removed by needle aspiration biopsy. For this, a fine needle attached to a syringe is inserted through the skin and into the organ or tissue of interest. The needle is typically guided to the region of interest using ultrasound or computed tomography (CT) imaging. Once the needle is inserted into the tissue, a vacuum is created with the syringe such that cells or fluid may be sucked through the needle and collected in the syringe. A sample of cells or tissue may also be removed by incisional or core biopsy. For this, a cone, a cylinder, or a tiny bit of tissue is removed from the region of interest. This type of biopsy is generally guided by CT imaging, ultrasound, or an endoscope. Lastly, the entire cancerous tumor may be removed by excisional biopsy or surgical resection.

[00420] RNA, protein, or DNA may be extracted from the biopsied cells or tissue to permit analysis of the expression of a molecular marker using methods described above in section (l)(d). The biopsied cells or tissue may also be embedded in plastic or paraffin, from which nucleic acids may be isolated. The expression of a molecular marker may also be performed in the biopsied cells or tissue in situ {e.g., in situ hybridization, immunohistochemistry).

[00421] Expression of a molecular marker may also be examined in vivo in a subject. A particular mRNA or protein may be labeled with fluorescent dye, a bioluminescent marker, a fluorescent semiconductor nanocrystal, or a short-lived radioisotope, and then the subject may be imaged or scanned using a variety of techniques, depending upon the type of label.

Methods for Predicting or Determining Responsiveness to a HDAC Inhibitor

[00422] The present disclosure also provides methods for predicting responsiveness of a subject with a disease or disorder to treatment with a histone deacetylase (HDAC) inhibitor by obtaining a biological sample {e.g., a formalin fixed paraffin embedded tissue) from the subject; assaying the biological sample for expression of one or more miRNAs {e.g., one or more of MiR-17, MiR-18A, Mir18B, Mir19A, Mir19B1 , Mir19B2, Mir20A, Mir92A1 , Mir92A2, Mir106A or Mir20B) (using for example ISH) and/or c-myc and/or a c-myc amplification {e.g., 3, 4, 5, 6 ,7, 8, 9 or 10 copies of c-myc per cell); determining if expression of the one or more miRNAs and/or c-myc in the cell is elevated or reduced compared to a control sample or above or below a threshold; determining if c-myc is amplified in the biological sample as compared to a control sample or above or below a threshold; and employing the determination of the expression of the one or more miRNAs and/or c-myc and/or c-myc amplification in the biological sample to predict responsiveness of the subject to the HDAC inhibitor.

[00423] The subject may be predicted to be responsive to the HDAC inhibitor where expression of the one or more miRNAs and/or c-myc and/or c-myc amplification in the biological sample is elevated as compared to the control sample or is greater than the threshold. Alternatively, the subject may be predicted to not be responsive to the HDAC inhibitor where expression of the one or more miRNAs and/or c-myc and/or c-myc amplification in the biological sample is reduced as compared to the control sample or is less than the threshold. In some embodiments, the threshold is set at a level of one or more miRNAs and/or c-myc expression and/or c-myc amplification above which a subject is known to respond to treatment with the HDAC inhibitor and below which a subject is known to not respond to treatment with the HDAC inhibitor. The threshold may be set at a level of one or more miRNAs and/or c-myc expression and/or c-myc amplification above which 50%, 60%, 70%, 80%, 90%, 95%, or greater of subject(s) respond to treatment with the HDAC inhibitor. Alternatively, the threshold may be set at a level of one or more miRNAs and/or c-myc expression and/or c-myc amplification above which 50%, 60%, 70%, 80%, 90%, 95%, or greater of subject(s) do not respond to treatment with the HDAC inhibitor. Alternatively, in some embodiments, the threshold is set at a level of one or more miRNAs and/or c-myc expression and/or c-myc amplification above which a subject is known to respond to treatment with the HDAC inhibitor and below which a subject is known to not respond to treatment with the HDAC inhibitor. The threshold may be set at a level of one or more miRNAs and/or c-myc expression and/or c-myc amplification below which 50%, 60%, 70%, 80%, 90%, 95%, or greater of subject(s) respond to treatment with the HDAC inhibitor. Alternatively, the threshold may be set at a level of one or more miRNAs and/or c-myc expression and/or c-myc amplification below which 50%, 60%, 70%, 80%, 90%, 95%, or greater of subject(s) do not respond to treatment with the HDAC inhibitor. For example, a threshold may be set at the maximum amount of expression of one or more miRNAs and/or c-myc and/or c-myc amplification in a biological sample obtained from a subject where the subject is responsive to treatment with a HDAC inhibitor. A threshold as provided herein may be an average or median obtained from two or more subjects.

[00424] In some embodiments, the subject may be predicted to be responsive to a HDAC inhibitor where the amount of one or more miRNAs (e.g., one or more of miR-17, miR-20a, miR18a, miR19a, miR-19b or miR92a) and/or c-myc expressed in a biological sample (e.g., tumor cells in the biological sample) is 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 100%, 200% or more than the amount of expression of one or more miRNAs (e.g., one or more of miR-17, miR- 20a, miR18a, miR19a, miR-19b or miR92a) and/or c-myc detected in a control sample. In some embodiments, the subject may be predicted to be responsive to a HDAC inhibitor where the amount of one or more miRNAs (e.g., one or more of miR-17, miR-20a, miR18a, miR19a, miR-19b or miR92a) and/or c-myc expressed in a biological sample (e.g., tumor cells in the biological sample) is 2 times, 3 times, 4 times, 5 times, 6 times, 7 times, 8 times, 9 times, 10 times or more than the amount of expression of one or more miRNAs (e.g., one or more of miR-17, miR-20a, miR18a, miR19a, miR-19b or miR92a) and/or c-myc detected in a control sample. In some embodiments, the biological sample and control sample are from the same specimen. In some embodiments, the biological sample and control sample are from the different specimens.

[00425] In some embodiments, the subject may be predicted to be responsive to a HDAC inhibitor where the amount of c-myc amplification (e.g., number of copies of the c-myc gene) in a biological sample (e.g., tumor cells in the biological sample) is 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 100%, 200% or more than the amount of c-myc amplification (e.g., number of copies of the c-myc gene) detected in a control sample. In some embodiments, the subject may be predicted to be responsive to a HDAC inhibitor where the amount of c-myc amplification (e.g., number of copies of the c-myc gene) in a biological sample (e.g., tumor cells in the biological sample) is 2 times, 3 times, 4 times, 5 times, 6 times, 7 times, 8 times, 9 times, 10 times or more than the amount of c-myc amplification (e.g., number of copies of the c-myc gene) detected in a control sample. In some embodiments, the biological sample and control sample are from the same specimen. In some embodiments, the biological sample and control sample are from the different specimens.

[00426] In some embodiments, the subject may be predicted to be responsive to a HDAC inhibitor where the amount of expression of one or more miRNAs (e.g., one or more of miR-17, miR-20a, miR18a, miR19a, miR-19b or miR92a) and/or c-myc expressed in a biological sample (e.g., tumor cells in the biological sample) is 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 100%, 200% or more than the amount of expression of one or more miRNAs (e.g., one or more of miR-17, miR-20a, miR18a, miR19a, miR-19b or miR92a) detected in a control sample and the amount of c-myc amplification in a biological sample (e.g., tumor cells in the biological sample) is 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 100%, 200% or more than the amount of c-myc amplification detected in a control sample. In some embodiments, the subject may be predicted to be responsive to a HDAC inhibitor where the amount of one or more miRNAs (e.g., one or more of miR-17, miR-20a, miR18a, miR19a, miR-19b or miR92a) and/or c-myc expressed in a biological sample (e.g., tumor cells in the biological sample) is 2 times, 3 times, 4 times, 5 times, 6 times, 7 times, 8 times, 9 times, 10 times or more than the amount of expression of one or more miRNAs (e.g., one or more of miR-17, miR-20a, miR18a, miR19a, miR-19b or miR92a) detected in a control sample and the amount of c-myc amplification in a biological sample (e.g., tumor cells in the biological sample) is 2 times, 3 times, 4 times, 5 times, 6 times, 7 times, 8 times, 9 times, 10 times or more than the amount of c-myc amplification detected in a control sample. In some embodiments, the biological sample and control sample are from the same specimen.

[00427] A determination of whether a subject will be predicted to be responsive to a HDAC inhibitor may be used to direct a therapeutic regimen for a particular disease or disorder including, for example, cancer. Such methods may comprise obtaining a biological sample from a subject; assaying the biological sample for expression of one or more miRNAs (e.g., one or more of miR-17, miR-20a, miR18a, miR19a, miR-19b or miR92a) and/or c-myc and/or a c-myc amplification (e.g., 3, 4, 5, 6 ,7, 8, 9 or 10 copies of c-myc per cell); determining if expression of the one or more miRNAs and/or c-myc in the cell is elevated or reduced compared to a control sample or above or below a threshold; determining if c-myc is amplified in the biological sample as compared to a control sample or above or below a threshold; employing the determination of the expression of the one or more miRNAs and/or c-myc and/or c-myc amplification in the biological sample to predict responsiveness of the subject to the HDAC inhibitor; and administering to the subject a therapeutically effective amount of a therapeutic regimen including, for example, one or more histone deacetylase (HDAC) inhibitors where the subject is predicted to be responsive to the HDAC inhibitor. The subject may be predicted to be responsive to the HDAC inhibitor where expression of the one or more miRNAs and/or c-myc in the biological sample and/or c-myc amplification is elevated as compared to the control sample or is greater than the threshold. Alternatively, the subject may be predicted to not be responsive to the HDAC inhibitor where expression of the one or more miRNAs and/or c-myc and/or c-myc amplification in the biological sample is reduced as compared to the control sample or is less than the threshold. The threshold may be set at a level of miRNA and/or c-myc expression and/or c-myc amplification in a control sample above which a subject is known to respond to treatment with the HDAC inhibitor and below which a subject is known to not respond to treatment with the HDAC inhibitor. In some embodiments, the threshold may be set at a level of miRNA and/or c-myc expression and/or c-myc amplification in the control sample above which 50%, 60%, 70%, 80%, 90%, 95%, or greater of subject(s) respond to treatment with the HDAC inhibitor. In some embodiments, the threshold is set at a level of miRNA and/or c-myc expression and/or c-myc amplification in the control sample below which 50%, 60%, 70%, 80%, 90%, 95%, or greater of subject(s) do not respond to treatment with the HDAC inhibitor.

[00428] The present disclosure also provides methods for determining if a subject with a disease or disorder is responding to treatment with a histone deacetylase (HDAC) inhibitor by obtaining a biological sample from the subject, assaying the biological sample for c-myc expression and/or c-myc amplification, determining if c-myc expression and/or c-myc amplification in the biological sample is increased or decreased as compared to a control sample or above or below a threshold, and employing the determination of c-myc expression and/or c-myc amplification in the biological sample to determine if the subject is responding to treatment with the HDAC inhibitor.

[00429] The subject may be determined to be responding to treatment with the HDAC inhibitor where expression of the one or more miRNAs and/or c-myc in the biological sample and/or c-myc amplification is elevated as compared to the control sample or is greater than the threshold. Alternatively, the subject may be determined to not be responding to the HDAC inhibitor where expression of the one or more miRNAs and/or c- myc and/or c-myc amplification in the biological sample is reduced as compared to the control sample or is less than the threshold. The threshold may be set at a level of miRNA and/or c-myc expression and/or c-myc amplification in a control sample above which a subject is known to respond to treatment with the HDAC inhibitor and below which a subject is known to not respond to treatment with the HDAC inhibitor. In some embodiments, the threshold may be set at a level of miRNA and/or c-myc expression and/or c-myc amplification in the control sample above which 50%, 60%, 70%, 80%, 90%, 95%, or greater of subject(s) respond to treatment with the HDAC inhibitor. In some embodiments, the threshold is set at a level of miRNA and/or c-myc expression and/or c-myc amplification in the control sample below which 50%, 60%, 70%, 80%, 90%, 95%, or greater of subject(s) do not respond to treatment with the HDAC inhibitor.

Pharmaceutical Compositions

[00430] The HDAC inhibitor can be administered as an active ingredient in admixture with suitable pharmaceutical diluents, excipients, or carriers (collectively referred to herein as "carrier" materials) suitably selected with respect to the intended form of administration, that is, oral tablets, capsules, elixirs, syrups and the like, and consistent with conventional pharmaceutical practices.

[00431 ] For example, in one embodiment, the pharmaceutical composition comprises the HDAC inhibitor PXD-101 in solution with L-arginine. To prepare this composition, a 10 g quantity of L-arginine was added to a vessel containing approximately 70 ml. of Water-For-lnjections BP. The mixture was stirred with a magnetic stirrer until the arginine had dissolved. A 5 g quantity of PXD-101 was added, and the mixture stirred at 25°C until the PXD-101 had dissolved. The solution was diluted to a final volume of 100 ml_ using Water-For-lnjections BP. The resulting solution had a pH of 9.2-9.4 and an osmolality of approximately 430 mOSmol/kg. The solution was filtered through a suitable 0.2 sterilizing (e.g., PVDF) membrane. The filtered solution was placed in vials or ampoules, which were sealed by heat, or with a suitable stopper and cap. The solutions were stored at ambient temperature, or, more preferably, under refrigeration (e.g., 2-8°C) in order to reduced degradation of the drug.

[00432] In one embodiment, the HDAC inhibitor (e.g., PXD-101 ) can be administered orally. Oral administration can be in the form of a tablet or capsule. The HDAC inhibitor can be combined with an oral, non-toxic, pharmaceutically acceptable, inert carrier such as lactose, starch, sucrose, glucose, methyl cellulose, microcrystalline cellulose, sodium croscarmellose, magnesium stearate, dicalcium phosphate, calcium sulfate, mannitol, sorbitol and the like or a combination thereof. For oral administration in liquid form, the H DAC inhibitor can be combined with any oral, non-toxic, pharmaceutically acceptable inert carrier such as ethanol, glycerol, water and the like. Moreover, when desired or necessary, suitable binders, lubricants, disintegrating agents and coloring agents can also be incorporated into the mixture. Suitable binders include starch, gelatin, natural sugars such as glucose or beta-lactose, corn-sweeteners, natural and synthetic gums such as acacia, tragacanth or sodium alginate, carboxymethylcellulose, microcrystalline cellulose, sodium croscarmellose, polyethylene glycol, waxes and the like. Lubricants suitable for use in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, and the like. Disintegrators suitable for use in these dosage forms include starch methyl cellulose, agar, bentonite, xanthan gum and the like.

[00433] Suitable pharmaceutically acceptable salts of the H DAC inhibitors described herein, and suitable for use in the method of the invention, are conventional non-toxic salts and can include a salt with a base or an acid addition salt such as a salt with an inorganic base, for example, an alkali metal salt (e.g., lithium salt, sodium salt, potassium salt, etc.), an alkaline earth metal salt (e.g., calcium salt, magnesium salt, etc.), an ammonium salt; a salt with an organic base, for example, an organic amine salt (e.g., triethylamine salt, pyridine salt, picoline salt, ethanolamine salt, triethanolamine salt, dicyclohexylamine salt, N 1 N'- dibenzylethylenediamine salt, etc.) etc.; an inorganic acid addition salt (e.g., hydrochloride, hydrobromide, sulfate, phosphate, etc.); an organic carboxylic or sulfonic acid addition salt (e.g., formate, acetate, trifluoroacetate, maleate, tartrate, methanesulfonate, benzenesulfonate, p-toluenesulfonate, etc.); a salt with a basic or acidic amino acid (e.g., arginine, aspartic acid, glutamic acid, etc.) and the like.

[00434] Various further aspects and embodiments of the present invention will be apparent to those skilled in the art in view of the present disclosure. All documents and database entries mentioned in this specification are incorporated herein by reference in their entirety, "and/or" where used herein is to be taken as specific disclosure of each of the two specified features or components with or without the other. For example "A and/or B" is to be taken as specific disclosure of each of (i) A, (ii) B and (iii) A and B, just as if each is set out individually herein.

[00435] The HDAC inhibitor can be administered in an oral form, for example, as tablets, capsules (each of which includes sustained release or timed release formulations), pills, powders, granules, elixirs, tinctures, suspensions, syrups, and emulsions, all well known to those of ordinary skill in the pharmaceutical arts. Likewise, the HDAC inhibitor can be administered in intravenous (bolus or infusion), intraperitoneal, subcutaneous, or intramuscular form, well known to those of ordinary skill in the pharmaceutical arts.

[00436] The HDAC inhibitor can be administered in the form of a depot injection or implant preparation that can be formulated in such a manner as to permit a sustained release of the active ingredient. The active ingredient can be compressed into pellets or small cylinders and implanted subcutaneously or intramuscularly as depot injections or implants. Implants can employ inert materials such as biodegradable polymers or synthetic silicones, for example, Silastic, silicone rubber or other polymers manufactured by the Dow- Corning Corporation.

[00437] The HDAC inhibitor can also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles. Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine, or phosphatidylcholines.

[00438] The HDAC inhibitor can also be delivered by the use of monoclonal antibodies as individual carriers to which the compound molecules are coupled.

[00439] The HDAC inhibitor can also be prepared with soluble polymers as targetable drug carriers. Such polymers can include polyvinylpyrrolidone, pyran copolymer, polyhydroxy-propyl- methacrylamide-phenol, polyhydroxyethyl-aspartamide-phenol, or polyethyleneoxide- polylysine substituted with palmitoyl residues.

[00440] Furthermore, the HDAC inhibitor can be prepared with biodegradable polymers useful in achieving controlled release of a drug, for example, polylactic acid, polyglycolic acid, copolymers of polylactic and polyglycolic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates, and cross linked or amphipathic block copolymers of hydrogels. The dosage regimen utilizing the HDAC inhibitor can be selected in accordance with a variety of factors including type, species, age, weight, sex and the type of cancer being treated; the severity (i.e., stage) of the cancer to be treated; the route of administration; the renal and hepatic function of the subject; and the particular compound or salt thereof employed. An ordinarily skilled physician or veterinarian can readily determine and prescribe the effective amount of the drug required to treat, for example, to prevent, inhibit (fully or partially) or arrest the progress of the disease.

[00441] Oral dosages of the HDAC inhibitor, when used to treat the desired cancer can range between about 2 mg to about 6000 mg per day, such as from about 20 mg to about 6000 mg per day, such as from about 200 mg to about 6000 mg per day. For example, oral dosages can be about 2, about 20, about 200, about 400, about 800, about 1200, about 1600, about 2000, about 4000, about 5000 or about 6000 mg per day. It is understood that the total amount per day can be administered in a single dose or can be administered in multiple dosing such as twice, three or four times per day.

[00442] For example, a subject can receive between about 2 mg/day to about 2000 mg/day, for example, from about 20 to about 2000 mg/day, such as from about 200 to about 2000 mg/day, for example from about 400 mg/day to about 1200 mg/day. A suitably prepared medicament for once a day administration can thus contain between about 2 mg and about 2000 mg, such as from about 20 mg to about 2000 mg, such as from about 200 mg to about 1200 mg, such as from about 400 mg/day to about 1200 mg/day. The HDAC inhibitor can be administered in a single dose or in divided doses of two, three, or four times daily. For administration twice a day, a suitably prepared medicament would therefore contain half of the needed daily dose.

[00443] Intravenously or subcutaneously, the subject would receive the HDAC inhibitor (e.g., PXD- 101 ) in quantities sufficient to deliver between about 3-1500 mg/m2 per day, for example, about 3, 30, 60, 90, 180, 300, 600, 900, 1000, 1200, or 1500 mg/m2 per day. Such quantities can be administered in a number of suitable ways, e.g., large volumes of low concentrations of HDAC inhibitor during one extended period of time or several times a day. The quantities can be administered for one or more consecutive days, intermittent days, or a combination thereof per week (7 day period). Alternatively, low volumes of high concentrations of HDAC inhibitor during a short period of time, e.g., once a day for one or more days either consecutively, intermittently, or a combination thereof per week (7 day period). For example, a dose of 300 mg/m2 per day can be administered for 5 consecutive days for a total of 1500 mg/m2 per treatment. In another dosing regimen, the number of consecutive days can also be 5, with treatment lasting for 2 or 3 consecutive weeks for a total of 3000 mg/m2 and 4500 mg/m2 total treatment.

[00444] Typically, an intravenous formulation can be prepared which contains a concentration of HDAC inhibitor of from about 1 .0 mg/mL to about 10 mg/mL, e.g., 2.0 mg/mL, 3.0 mg/mL, 4.0 mg/mL, 5.0 mg/mL, 6.0 mg/mL, 7.0 mg/mL, 8.0 mg/mL, 9.0 mg/mL, or 10 mg/mL, and administered in amounts to achieve the doses described above. In one example, a sufficient volume of intravenous formulation can be administered to a subject in a day such that the total dose for the day is between about 300 and about 1200 mg/m2.

[00445] In a preferred embodiment, 1000 mg/m2 of PXD-101 is administered intravenously once daily by 30-minute infusion every 24 hours for at least five consecutive days.

[00446] In one embodiment, PXD-101 is administered in a total daily dose of up to 1500 mg/m2. In one embodiment, PXD-101 is administered intravenously in a total daily dose of 1000 mg/m2, or 1400 mg/m2 or 1500 mg/m2, for example, once daily, continuously (every day), or intermittently. In one embodiment, PXD-101 is administered every day on days 1 to 5 every three weeks.

[00447] Glucuronic acid, L-lactic acid, acetic acid, citric acid, or any pharmaceutically acceptable acid/conjugate base with reasonable buffering capacity in the pH range acceptable for intravenous administration of the HDAC inhibitor can be used as buffers. Sodium chloride solution wherein the pH has been adjusted to the desired range with either acid or base, for example, hydrochloric acid or sodium hydroxide, can also be employed. Typically, a pH range for the intravenous formulation can be in the range of from about 5 to about 12. A preferred pH range for intravenous formulation wherein the HDAC inhibitor has a hydroxamic acid moiety (e.g., as in PXD-101 ), can be about 9 to about 12. Consideration should be given to the solubility and chemical compatibility of the HDAC inhibitor in choosing an appropriate excipient.

[00448] Subcutaneous formulations, preferably prepared according to procedures well known in the art at a pH in the range between about 5 and about 12, also include suitable buffers and isotonicity agents. They can be formulated to deliver a daily dose of HDAC inhibitor in one or more daily subcutaneous administrations, e.g., one, two or three times each day. The choice of appropriate buffer and pH of a formulation, depending on solubility of the HDAC inhibitor to be administered, is readily made by a person having ordinary skill in the art. Sodium chloride solution wherein the pH has been adjusted to the desired range with either acid or base, for example, hydrochloric acid or sodium hydroxide, can also be employed in the subcutaneous formulation. Typically, a pH range for the subcutaneous formulation can be in the range of from about 5 to about 12. A preferred pH range for subcutaneous formulation wherein the HDAC inhibitor has a hydroxamic acid moiety is about 9 to about 12. Consideration should be given to the solubility and chemical compatibility of the HDAC inhibitor in choosing an appropriate excipient.

[00449] The HDAC inhibitor can also be administered in intranasal form via topical use of suitable intranasal vehicles, or via transdermal routes, using those forms of transdermal skin patches well known to those of ordinary skill in that art. To be administered in the form of a transdermal delivery system, the administration will likely be continuous rather than intermittent throughout the dosage regime.

[00450] The further chemotherapeutic agent (or agents, if more than one is employed) may be administered using conventional methods and protocols well known to those of skill in the art. For example, a typical dosage rate for 5-fluorouracil (5-FU) is 750- 1000 mg/m2 in a 24 hour period, administered for 4-5 days every 3 weeks. A typical dose rate for capecitabine is 1000 to 1250 mg/m2 orally, when administered twice daily on days 1 to 14 of every 3rd week. [00451] Without further description, it is believed that one of ordinary skill in the art may, using the preceding description and the following illustrative examples, make and utilize the agents of the present disclosure and practice the claimed methods. The following working examples are provided to facilitate the practice of the present disclosure, and are not to be construed as limiting in any way the remainder of the disclosure.

EXAMPLES

Example 1 : Methods and materials

Cell lines, tissue culture and reagents

[00452] SW620, AU565, MDA-MB-231 and MCF-7 were purchased from American Type Culture Collection (ATCC, Manassas, VA). Cells were grown in the media suggested by ATCC. All cells were maintained in the media containing 10% fetal bovine serum, penicillin (100U/ml), and streptomycin (100mg/ml), and cultured at 37°C in humidified 5% C0₂. Cells were harvested and applied for studies before passage 15 and at confluency of 70%. Histone deacetylase inhibitors Vorinostat (SAHA), MS-275, LAQ824 were purchased from Selleck Chemicals. MicroRNA purification miRNeasy™ kits were purchased from Qiagen.

Bioinformatics process

[00453] MicroRNA data sets were applied to Ingenuity Pathway Analysis (I PA) systems for signaling transduction pathway assessment.

MiRNA Assays

[00454] Cells were treated for 24 hours with either DMSO, 0.1 μΜ LAQ824, 2.5 μΜ MS-275, or 10 μΜ LAQ824. ^Concentrations were selected by identifying levels needed to induce optimal p21 and/or acetylated histone H3 expression).

[00455] After treatment, cells were harvested for miRNA extraction. The miRNeasy™ mini kit (Qiagen) was used to extract miRNA by following the instructions provided by the manufacturer. Product purity and quality were monitored with NanoDrop™ spectrophotometer. Concentrations of total RNA (including microRNA and mRNA) in the samples were between 1 .2~3.3μ9/μΙ.

[00456] MicroRNA samples were sent to University of California Los Angeles core facility for conducting Exiqon miRCURY LNA™ miRNA array.

Quantitative reverse transcription polymerase chain reaction (qRT-PCR)

[00457] cDNA reverse transcription was done on untreated cells or those treated for 24 hours with HDACi using ABI's Multi Scribe Reverse Transcriptase™ and PCR was performed on ABI's 7900HT fast real-time PCR system using ABI Taqman™ miR arrays for MIR17, MIR18A, and MIR19A, MIR20A, MIR20B, MIR106, and RUN6 (internal control). Western blotting

[00458] Western blot analysis of cell lysates was performed using standard procedures. Cells treated with or without various concentrations of SAHA, MS-275, and LAQ824 for 24 hours were lysed using RIPA buffer composed of protease inhibitor cocktail (Sigma), PMSF (Sigma), and phosphoguard A and B (Quintiles TMD). Cell lysates were sonicated and centrifuged to remove debris. Western Blots were performed using primary antibody to bim, c-myc (Cell Signaling), acetyl-H3 (Millipore), and actin (Sigma). Western blot images were obtained on LICORE's Odyssey Infrared Imaging System™.

[00459] Growth studies were performed on treated cells using Cyquant™ (Invitrogen) assays on a Biotek microplate reader.

Apoptosis assays

[00460] Apoptosis studies were performed on a flow cytometer using an annexin V assay (BD). Following treatment cells (and supernatants) were harvested and washed twice with cold PBS and resuspended at a concentration of 100,000 cells/100 μΙ in 1X Annexin Binding Buffer (ABB). Cells were then stained with PE-conjugated annexin and 7-Amino- Actinomyocin (7-ADD). Analysis was performed on a BD FACS Canto II™ flow cytometer. Early (low 7-ADD/highPE stained cells) and late (high 7-ADD, high PE stained cells) apoptotic cells were combined for a single apoptosis value.

AntagomiR experiments

[00461] 30 -100 nM antagomiRs for miR-18, miR-19, miR-20, let7C (positive control), and a scrambled miR sequence (negative control) (Ambion) were reverse transfected into cells using siPORT™ transfection reagent (Ambion). 24 hours after transfection of antagomiRs, cells were collected and RNA was extracted using the miRNeasy™ mini kit (Qiagen). Expression of Bim was determined by RT-PCR as described previously. 24, 48, and 72 hours after transfection of antagomiRs, cells (on 96-well plates) were incubated for 30 min at 37° in a Hoeschst-staining solution followed by a 30 minute incubation in a fixative solution at room temperature. Cells were then washed with PBS and 200 μΙ PBS was added to each well prior to analyzing on the Cellomics Arrayscan™ high throughput machine used to assess the total number of Hoeschst-stained cells.

Example 2: MiRNA array reveals down-regulation of members of the miR-17~92 family and its homologs by HDAC inhibitors in MDA-MB-231 and MCF-7 cells

[00462] A miRNA microarray analysis was performed on MCF-7 and MDA-MB-231 breast cancer cells treated for 24 hours with the HDAC inhibitors SAHA, MS-275, or LAQ824. In contrast to LAQ824 which inhibits HDAC -1 -,2, -3, -5, -6, -7, -8, -9, -10 and -1 1 and SAHA which inhibits the same HDACs (excluding HDAC -1 1 ), MS-275 is a more selective HDACi which preferentially inhibits HDACs-1 ,-2,-3, and -9. To determine the optimum concentration of an HDACI to use for treatment of the cells; the cells were treated with increasing concentration of each HDACI and western blots were performed to assess the expression of acetyl-histone-H3 and p21 , two well-known targets induced by these compounds (FIG. 1 ). The lowest concentration of drugs that were maximally effective in both cell lines were 10.0 μΜ SAHA, 2.5 μΜ MS-275, and 0.1 μΜ LAQ824. These concentrations were selected to treat cells and then conduct a miRNA microarray analysis.

[00463] Upon treatment of MCF-7 and MDA-MB-231 breast cancer cells with an optimized concentration of HDACI (determined above), there was a considerable decrease in the expression of several members of the oncogenic miR-17~92 cluster including miR-17 and miR-20A with all three treatments (SAHA, MS-275, and LAQ824) in both cell lines, miR- 18A (with all except SAHA treatment in MDA-MB-231 cells), and miR-19A (with all except LAQ824 treatment in MCF-7 cells) (FIG. 2). MiR-92 was only down-regulated with SAHA treatment in MDA-MB-231 cells. Interestingly, several of the homologs of the miR-17~92 cluster including miR-106A (with all except SAHA treatment in MDA-MB-231 cells), miR-18B (with all treatments in both cell lines), and miR-20B (with all treatments but only in MCF-7 cells) were also down-regulated with HDACI treatment.

[00464] RT-PCR was performed to confirm the miRNA microarray data (FIG. 3A and 3B). MS-275 reduced the expression of miR-18A and miR-19A in MCF-7 cells. Although reduced expression of miR-18A and miR-19A were not shown with SAHA treatment in MDA- MB-231 and MCF-7 cells, respectively, in the miRNA microarrays. RT-PCR assays demonstrated a decrease in the expression of both miR-18A and miR-19A as well as miR- 20A with both SAHA and LAQ824 treatment in both cell types (FIG. 3A and 3B). The expression of miR-17 was also confirmed to be decreased by treatment with SAHA in both cell types and with LAQ824 in MCF-7 cells.

Example 3: Identification of cells expressing high levels of the miR-17-92 cluster

[00465] The NCI-60 dataset (a publically available dataset from NCI containing both mRNA and mirRNA data from 60 commonly used cancer cell lines) was interrogated to identify cell lines that demonstrate a high expression of the MIR-17-92 cluster. In addition to lymphoma cells, it was discovered that colon cells (e.g., SW620, HCT1 16, and COLO205) express high levels of the mir-17-92 cluster (FIG. 4). Moreover, FISH was used to determine additional cell lines that have high levels of c-myc expression. Such identified cell lines included AU565, H460, and SW620 among others (FIG. 5). [00466] Subsequently, RT-PCR analysis was performed on the cell lines identified by both the NCI-60 data and the FISH data that express high levels of c-myc to determine the basal level of expression of MIR-17, MIR-18A, MIR-19A, and MIR-20A of the MIR-17-92 cluster. Compared to other cells, SW620 and COLO205 colon cells and AU565 breast cancer cells all showed high expression of the MIR-17-92 cluster and particularly of MIR- 18A, MIR-19A and MIR-20A (FIG. 6).

Example 4: Basal expression of the miR-17-92 cluster in mvc amplified cells

[00467] The basal expression level of the miR-17-92 cluster in MDA-MB-231 and MCF-7 cells was compared with two cells (AU565 breast cancer cells and SW620 colon cancer cells) which are identified as myc amplified by the COSMIC database. Although all four cell lines expressed some level of miR-18, miR-19, and miR-20, there was significantly higher levels of all three miRs in the myc amplified AU565 and SW620 cells (FIG. 7).

Example 5: Mvc amplified cells are more sensitive to HDACI treatment

[00468] Growth studies were performed on AU565, SW620, MCF-7 and MDA-MB- 231 cells treated two days with DMSO or increasing concentrations of SAHA, MS-275, or LAQ824. With all three HDACi treatments, myc amplified AU565 and SW620 cells responded better than myc unamplified MCF-7 and MDA-MB-231 cells (FIG. 8 and 9). Notably, LAQ824 was substantially more potent than either of the other HDACI while MS- 275 was least potent. Additionally, the Gl₅₀ of LAQ824 and SAHA was determined in 14 different cell lines (7 myc amplified cell lines and 7 myc unamplified cell lines). The results indicated that myc amplified cells are more sensitive to SAHA and LAQ824 than cells without myc amplification (FIG. 10 and 1 1 ).

[00469] To determine if enhanced cell kill by HDACI in myc amplified cells correlated to enhanced apoptosis, PARP cleavage was measured in AU565, SW620, MCF-7 and MDA-MB-231 cells treated for 24 hours with DMSO or increasing concentrations of SAHA and LAQ824. As expected, there was more PARP cleavage in myc amplified AU565 and SW620 cells than myc unamplified MDA-MB-231 and MCF-7 cells (FIG. 12).

Example 6: HDACI treatment decreases the expression of miR-18A, miR-19A, and miR - 20A in SW620 and AU565 cells

[00470] To determine if HDACI had the same effect on the expression of the miR- 17-92 cluster in myc amplified cells, RT-PCR analysis was performed to determine the expression level of the miR-17~92 cluster in SW620 and AU565 cells treated with SAHA, MS-275, or LAQ824. Although all tested HDACIs were effective at decreasing the expression of the miRs in AU565 cells, only SAHA and LAQ824 were effective in SW620 cells (FIG. 13A and 13B). MS-275 significantly reduced the expression of miR-18 and miR- 19, but was not able to effectively reduce the expression of miR-17 and miR-20 in SW620 cells.

Example 7: HDACI treatment decreases c-myc, a regulator of the miR-17~92 cluster, and increases Bim, a target of the miR-17~92 cluster, in cancer cells

[00471] The expression of c-myc and targets of the miR-17~92 cluster were examined in HDACI treated cells. Western blots were performed on lysates isolated from AU565, SW620, MCF-7 and MDA-MB-231 cells that were treated with DMSO or increasing concentrations of SAHA or LAQ824 for 24 hours. Treatment with either HDACi resulted in a dose dependent decrease in the expression of c-myc in all four cell lines (FIG. 14A and14 B). The concentration required to induce this effect was similar among all the cell lines. The miR-17~92 cluster has been shown to inhibit the expression of several targets which negatively impact cellular proliferation, including the E2F1 (Sylvestre et al. (2007) J Biol Chem, 282(4): p. 2135-43; Woods et al. (2007) J Biol Chem, 2007. 282(4): p. 2130-4) PTEN (Mu et al. (2009) Genes Dev 23(24): p. 2806-1 1 ; Olive et al. (2009) Int J Biochem Cell Biol 42(8): p. 1348-54; Takakura et al. (2008) Cancer Sci 99(6): p. 1 147-54; Xiao et al. (2008) Nat Immunol. 9(4): p. 405-14), p21 (Fontana et al. (2008) PLoS One 3(5): p. e2236), and Bim (Xiao et al. (2008) Nat Immunol. 9(4): p. 405-14; Petrocca et al. (2008) Cancer Res 68(20): p. 8191 -4; Ventura et al. (2008) Cell 132(5): p. 875-86). Although there was no change in the expression of either E2F1 or PTEN with HDACi treatment (data not shown), there was a dose dependent increase in the expression of both p21 and Bim in treated cells. Interestingly, Bim was basally overexpressed in MCF-7 cells and treatment with HDACI did not significantly change its expression. There was a significant decrease in the expression of Bim and p21 in AU565 cells with 10 μΜ LAQ824 (relative to lower doses) probably due to excessive cell death.

[00472] Myc amplification is directly related to the expression of the miR-17~92 cluster, we measured the expression of miR-18, miR-19, and miR-20 in seven myc amplified as compared to seven myc unamplified cells (FIG. 15).

Example 8: Inhibition of members of the miR-17~92 family induces the expression of Bim

[00473] Several studies have shown that one mechanism by which the miR-17~92 cluster inhibits apoptosis is by inhibiting the expression of the pro-apoptotic target Bim (Xiao et al. (2008) Nat Immunol 9(4): p. 405-14; Petrocca et al. (2008) Cancer Res 68(20): p. 8191 -4; Ventura et al. (2008) Cell 132(5): p. 875-86). To confirm the miR-17-92 cluster inhibits the expression of Bim, Bim expression was measured by RT-PCR in AU565 and SW620 cells transfected with antagomiRs against miR-18, miR-19, or miR-20. Inhibition of any of these miRs was sufficient to significantly induce Bim expression in SW620 cells, while inhibition of miR-19 or miR-20 (but not miR-18) induced Bim expression in AU565 cells (FIG. 16). These results confirm that the miR-17~92 cluster plays a role in the inhibition of Bim in these cells.

Example 9: Determining responsiveness of a mammalian subject to treatment with a HDACI

[00474] The success of therapeutics in medicine and especially in a complex disease such as cancer depends on the correct diagnosis choice of patients treated with a drug. This process requires knowledge of the specific patient markers that can be used to predict how the patient will respond to a given drug or class of drugs that share a common mechanism of action. The inventors of the instant application have shown that patients with increased expression of miRNAs and/or c-myc amplification respond to treatment with a HDAC inhibitor while patients not expressing (or expressing low levels of) miRNA and/or c- myc amplification did not respond to treatment with a HDACI. A mammalian tumor likely to be responsive to a HDAC inhibitor may be identified as follows.

[00475] Briefly, a biological sample was removed from a patient prior to treatment with a HDAC inhibitor and analyzed for expression of one or more miRNAs such as one or more of miR-17, miR-20a, miR18a, miR19a, miR-19b or miR92a (or their homologues) and/or c-myc amplification. The patient sample consisted of a tumor biopsy. The biological sample was then analyzed for miRNA expression and/or c-myc amplification. Patient samples which exhibited miR-17, miR-20a, miR18a, miR19a, miR-19b or miR92a expression above that of a control sample and/or c-myc amplification greater than that of a control sample were responsive to treatment with HDAC inhibitors including, for example, SAHA, LAQ824 or MS-275. Conversely, patient samples which exhibited miR-17, miR-20a, miR18a, miR19a, miR-19b or miR92a expression below that of a control sample and/or c- myc amplification less than that of a control sample were not responsive to treatment with HDAC inhibitors including, for example, SAHA, LAQ824 or MS-275. Therefore, patients in which a biological sample was obtained that exhibit expression of miRNA and or c-myc amplification above the level detected in a control sample may be predicted to not respond to treatment with a HDAC inhibitor while patients that do not express (or express reduced levels of) miRNA and/or c-myc amplification may be predicted to not respond to treatment with a HDACI. [00476] Aspects, including embodiments, of the present subject matter described above may be beneficial alone or in combination, with one or more other aspects or embodiments. Without limiting the foregoing description, in accordance with one aspect of the subject matter herein, there are provided methods for predicting sensitivity of a test cell to a histone deacetylase (HDAC) inhibitor, the method comprising: obtaining a test cell; assaying the test cell for expression of one or more miRNAs; determining if expression of the one or more miRNAs in the test cell is elevated or reduced compared to a control cell or above or below a threshold; and employing the determination of the expression of the one or more miRNAs in the test cell to predict sensitivity of the test cell to the HDAC inhibitor.

[00477] Without limiting the foregoing description, in accordance with one aspect of the subject matter herein, there are provided methods for predicting the sensitivity (e.g., responsiveness) of a cell and/or biological sample obtained from a subject (e.g., a human patient) to a histone deacetylase (HDAC) inhibitor and methods for determining if a subject is responding to treatment with a HDAC inhibitor. Such methods may comprise detecting the presence (e.g., expression) of one or more biomarkers including, one or more miRNAs (e.g., one or more of MiR-17, MiR-18A, Mir18B, Mir19A, Mir19B1 , Mir19B2, Mir20A, Mir92A1 , Mir92A2, Mir106A or Mir20B) and/or c-myc expression and/or a c-myc amplification (e.g., 3, 4, 5, 6 ,7, 8, 9 or 10 copies of c-myc per cell), in the cell and/or biological sample. The methods may be used to predict or determine the responsiveness of a subject to treatment with a HDAC inhibitor.

[00478] Without limiting the foregoing description, in accordance with another aspect of the subject matter herein, there are provided methods for predicting sensitivity of a test cell to a histone deacetylase (HDAC) inhibitor by obtaining a test cell; assaying the test cell for expression of one or more miRNAs; determining if expression of the one or more miRNAs in the test cell is elevated or reduced compared to a control cell or above or below a threshold; and employing the determination of the expression of the one or more miRNAs in the test cell to predict sensitivity of the test cell to the HDAC inhibitor.

[00479] In accordance with another aspect which may be used or combined with any of the preceding or following aspects, the miRNA is one or more of miR-17, miR-20a, miR18a, miR19a, miR-19b or miR92a.

[00480] In accordance with another aspect which may be used or combined with any of the preceding or following aspects, the miRNA is miRNA 17-92.

[00481 ] In accordance with another aspect which may be used or combined with any of the preceding or following aspects, the test cell is from a tumor.

[00482] In accordance with another aspect which may be used or combined with any of the preceding or following aspects, the tumor is a breast or colon tumor. [00483] In accordance with another aspect which may be used or combined with any of the preceding or following aspects, the test cell is from an aspirate, blood or serum.

[00484] In accordance with another aspect which may be used or combined with any of the preceding or following aspects, the test cell is from a cancer patient.

[00485] In accordance with another aspect which may be used or combined with any of the preceding or following aspects, the test cell is predicted to be sensitive to the HDAC inhibitor where expression of the one or more miRNAs in the test cell is elevated as compared to expression of the one or more miRNAs in the control cell or is above the threshold.

[00486] In accordance with another aspect which may be used or combined with any of the preceding or following aspects, the test cell is predicted to not be sensitive to the HDAC inhibitor where expression of the one or more miRNAs in the test cell is reduced as compared to expression of the one or more miRNAs in the control cell or is less than the threshold.

[00487] In accordance with another aspect whaich may be used or combined with any of the preceding or following aspects, the step of assaying the test cell for expression of one or more miRNAs is performed by in situ hybridization (ISH), Northern blot, qRT-PCR or microarray analysis.

[00488] In accordance with another aspect which may be used or combined with any of the preceding or following aspects, the threshold is set at a level of miRNA expression above which a cell is known to be sensitive to treatment with the HDAC inhibitor and below which a cell is known to not be sensitive to treatment with the HDAC inhibitor.

[00489] In accordance with another aspect which may be used or combined with any of the preceding or following aspects, the threshold is set at a level of miRNA expression below which a cell is known to be sensitive to treatment with the HDAC inhibitor and above which a cell is known to not be sensitive to treatment with the HDAC inhibitor.

[00490] In accordance with another aspect which may be used or combined with any of the preceding or following aspects, the threshold is set at a level of miRNA expression above which 50%, 60%, 70%, 80%, 90%, 95%, or greater of cells respond to treatment with the HDAC inhibitor.

[00491] In accordance with another aspect which may be used or combined with any of the preceding or following aspects, the threshold is set at a level of miRNA expression above which 50%, 60%, 70%, 80%, 90%, 95%, or greater of cells do not respond to treatment with the HDAC inhibitor.

[00492] In accordance with another aspect which may be used or combined with any of the preceding or following aspects, the threshold is set at a level of miRNA expression below which 50%, 60%, 70%, 80%, 90%, 95%, or greater of cells do not respond to treatment with the HDAC inhibitor.

[00493] In accordance with another aspect which may be used or combined with any of the preceding or following aspects, the threshold is set at a level of miRNA expression below which 50%, 60%, 70%, 80%, 90%, 95%, or greater of cells respond to treatment with the HDAC inhibitor.

[00494] In accordance with another aspect which may be used or combined with any of the preceding or following aspects, the control cell is the same cell type as the test cell.

[00495] In accordance with another aspect which may be used or combined with any of the preceding or following aspects, the control cell is a different cell type than the test cell.

[00496] Without limiting the foregoing description, in accordance with another aspect of the subject matter herein, there are provided methods for predicting responsiveness of a subject with a disease or disorder to a histone deacetylase (HDAC) inhibitor by obtaining a biological sample from the subject; assaying the biological sample for expression of one or more miRNAs; determining if expression of the one or more miRNAs in the biological sample is elevated or reduced compared to a control sample or above or below a threshold; and employing the determination of the expression of the one or more miRNAs in the biological sample to predict responsiveness of the subject to the HDAC inhibitor.

[00497] In accordance with another aspect which may be used or combined with any of the preceding or following aspects, the miRNA is one or more of miR-17, miR-20a, miR18a, miR19a, miR-19b or miR92a.

[00498] In accordance with another aspect which may be used or combined with any of the preceding or following aspects, the miRNA is miRNA 17-92.

[00499] In accordance with another aspect which may be used or combined with any of the preceding or following aspects, the HDAC inhibitor is a small molecule.

[00500] In accordance with another aspect which may be used or combined with any of the preceding or following aspects, the biological sample is from a tumor.

[00501] In accordance with another aspect which may be used or combined with any of the preceding or following aspects, the tumor is a breast or colon tumor.

[00502] In accordance with another aspect which may be used or combined with any of the preceding or following aspects, the biological sample is from an aspirate.

[00503] In accordance with another aspect which may be used or combined with any of the preceding or following aspects, the biological sample is from a cancer patient. [00504] In accordance with another aspect which may be used or combined with any of the preceding or following aspects, the subject is predicted to be responsive to the HDAC inhibitor where expression of the one or more miRNAs in the biological sample is elevated as compared to the control sample or is greater than the threshold.

[00505] In accordance with another aspect which may be used or combined with any of the preceding or following aspects, the subject is predicted to not be responsive to the HDAC inhibitor where expression of the one or more miRNAs in the biological sample is reduced as compared to the control sample or is less than the threshold.

[00506] In accordance with another aspect which may be used or combined with any of the preceding or following aspects, the step of assaying the biological sample for expression of one or more miRNAs is performed by in situ hybridization (ISH), Northern blot or microarray analysis.

[00507] In accordance with another aspect which may be used or combined with any of the preceding or following aspects, the threshold is set at a level of miRNA expression above which a subject is known to respond to treatment with the HDAC inhibitor and below which a subject is known to not respond to treatment with the HDAC inhibitor.

[00508] In accordance with another aspect which may be used or combined with any of the preceding or following aspects, the threshold is set at a level of miRNA expression below which a subject is known to respond to treatment with the HDAC inhibitor and above which a subject is known to not respond to treatment with the HDAC inhibitor.

[00509] In accordance with another aspect which may be used or combined with any of the preceding or following aspects, the threshold is set at a level of miRNA expression above which 50%, 60%, 70%, 80%, 90%, or 95% of subject(s) respond to treatment with the HDAC inhibitor.

[00510] In accordance with another aspect which may be used or combined with any of the preceding or following aspects, the threshold is set at a level of miRNA expression above which 50%, 60%, 70%, 80%, 90%, 95% or greater of subject(s) do not respond to treatment with the HDAC inhibitor.

[0051 1] In accordance with another aspect which may be used or combined with any of the preceding or following aspects, the threshold is set at a level of miRNA expression below which 50%, 60%, 70%, 80%, 90%, 95%, or greater of subject(s) respond to treatment with the HDAC inhibitor.

[00512] In accordance with another aspect which may be used or combined with any of the preceding or following aspects, the threshold is set at a level of miRNA expression below which 50%, 60%, 70%, 80%, 90%, 95%, or greater of subject(s) do not respond to treatment with the HDAC inhibitor. [00513] In accordance with another aspect which may be used or combined with any of the preceding or following aspects, the disease or disorder is cancer.

[00514] In accordance with another aspect which may be used or combined with any of the preceding or following aspects, the cancer is selected from the group consisting of gastrointestinal, prostate cancer, ovarian cancer, breast cancer, head and neck cancer, lung cancer, non-small cell lung cancer, cancer of the nervous system, kidney cancer, retina cancer, skin cancer, liver cancer, pancreatic cancer, genital-urinary cancer and bladder cancer.

[00515] In accordance with another aspect which may be used or combined with any of the preceding or following aspects, the subject is a cancer patient.

[00516] Without limiting the foregoing description, in accordance with another aspect of the subject matter herein, there are provided methods for treating a subject with a disease or disorder by obtaining a biological sample from a subject, assaying the biological sample for expression of one or more miRNAs, determining if expression of the one or more miRNAs in the biological sample is elevated or reduced compared to a control sample or above or below a threshold, employing the determination of the expression of the one or more miRNAs in the biological sample to predict responsiveness of the subject to the HDAC inhibitor, and administering to the subject a therapeutically effective amount of one or more histone deacetylase (HDAC) inhibitors where the subject is predicted to be responsive to the HDAC inhibitor.

[00517] In accordance with another aspect which may be used or combined with any of the preceding or following aspects, the miRNA is one or more of miR-17, miR-20a, miR18a, miR19a, miR-19b or miR92a.

[00518] In accordance with another aspect which may be used or combined with any of the preceding or following aspects, the miRNA is miRNA 17-92.

[00519] In accordance with another aspect which may be used or combined with any of the preceding or following aspects, the HDAC inhibitor is a small molecule.

[00520] In accordance with another aspect which may be used or combined with any of the preceding or following aspects, the biological sample is from a tumor.

[00521] In accordance with another aspect which may be used or combined with any of the preceding or following aspects, the tumor is a breast or colon tumor.

[00522] In accordance with another aspect which may be used or combined with any of the preceding or following aspects, the biological sample is from an aspirate.

[00523] In accordance with another aspect which may be used or combined with any of the preceding or following aspects, the biological sample is from a cancer patient. [00524] In accordance with another aspect which may be used or combined with any of the preceding or following aspects, the subject is predicted to be responsive to the HDAC inhibitor where expression of the one or more miRNAs in the biological sample is elevated as compared to the control sample or is greater than the threshold.

[00525] In accordance with another aspect which may be used or combined with any of the preceding or following aspects, the subject is predicted to not be responsive to the HDAC inhibitor where expression of the one or more miRNAs in the biological sample is reduced as compared to the control sample or is less than the threshold.

[00526] In accordance with another aspect which may be used or combined with any of the preceding or following aspects, the disease or disorder is cancer.

[00527] In accordance with another aspect which may be used or combined with any of the preceding or following aspects, the cancer is selected from the group consisting of gastrointestinal cancer, prostate cancer, ovarian cancer, breast cancer, head and neck cancer, lung cancer, non-small cell lung cancer, cancer of the nervous system, kidney cancer, retina cancer, skin cancer, liver cancer, pancreatic cancer, genital-urinary cancer and bladder cancer.

[00528] In accordance with another aspect which may be used or combined with any of the preceding or following aspects, the step of assaying the biological sample for expression of one or more miRNAs is performed by in situ hybridization (ISH), Northern blot or microarray analysis.

[00529] In accordance with another aspect which may be used or combined with any of the preceding or following aspects, the threshold is set at a level of miRNA expression above which a subject is known to respond to treatment with the HDAC inhibitor and below which a subject is known to not respond to treatment with the HDAC inhibitor.

[00530] In accordance with another aspect which may be used or combined with any of the preceding or following aspects, the threshold is set at a level of miRNA below which a subject is known to respond to treatment with the HDAC inhibitor and above which a subject is known to not respond to treatment with the HDAC inhibitor.

[00531] In accordance with another aspect which may be used or combined with any of the preceding or following aspects, the threshold is set at a level of miRNA expression above which 50%, 60%, 70%, 80%, 90%, 95%, or greater of subject(s) respond to treatment with the HDAC inhibitor.

[00532] In accordance with another aspect which may be used or combined with any of the preceding or following aspects, the threshold is set at a level of miRNA expression above which 50%, 60%, 70%, 80%, 90%, 95% or greater of subject(s) do not respond to treatment with the HDAC inhibitor. [00533] In accordance with another aspect which may be used or combined with any of the preceding or following aspects, the threshold is set at a level of miRNA expression below which 50%, 60%, 70%, 80%, 90%, 95%, or greater of subject(s) respond to treatment with the HDAC inhibitor.

[00534] In accordance with another aspect which may be used or combined with any of the preceding or following aspects, the threshold is set at a level of miRNA expression below which 50%, 60%, 70%, 80%, 90%, 95%, or greater of subject(s) do not respond to treatment with the HDAC inhibitor.

[00535] In accordance with another aspect which may be used or combined with any of the preceding or following aspects, the subject is a cancer patient.

[00536] In accordance with another aspect which may be used or combined with any of the preceding or following aspects, the therapeutically effective amount of one or more HDAC inhibitors are optionally adapted for a co-treatment with radiotherapy or radio- immunotherapy.

[00537] Without limiting the foregoing description, in accordance with another aspect of the subject matter herein, there are provided methods for selecting subjects for a clinical trial that are responsive to a histone deacetylase (HDAC) inhibitor by obtaining a biological sample from the subjects assaying the biological samples obtained from the subjects for expression of one or more miRNAs determining if expression of the one or more miRNAs in the biological sample is elevated or reduced compared to a control sample or above or below a threshold employing the determination of the expression of the one or more miRNAs in the biological sample to predict responsiveness of the subject to the HDAC inhibitor, and selecting subjects for inclusion in a clinical trial that are responsive to the HDAC inhibitor.

[00538] In accordance with another aspect which may be used or combined with any of the preceding or following aspects, the miRNA is one or more of miR-17, miR-20a, miR18a, miR19a, miR-19b or miR92a.

[00539] In accordance with another aspect which may be used or combined with any of the preceding or following aspects, the miRNA is miRNA 17-92.

[00540] In accordance with another aspect which may be used or combined with any of the preceding or following aspects, the HDAC inhibitor is a small molecule.

[00541] In accordance with another aspect which may be used or combined with any of the preceding or following aspects, the biological sample is from a tumor.

[00542] In accordance with another aspect which may be used or combined with any of the preceding or following aspects, the tumor is a breast or colon tumor. [00543] In accordance with another aspect which may be used or combined with any of the preceding or following aspects, the biological sample is from an aspirate.

[00544] In accordance with another aspect which may be used or combined with any of the preceding or following aspects, the biological sample is from a cancer patient.

[00545] In accordance with another aspect which may be used or combined with any of the preceding or following aspects, the subject is predicted to be responsive to the HDAC inhibitor where expression of the one or more miRNAs in the biological sample is elevated as compared to the control sample or is greater than the threshold.

[00546] In accordance with another aspect which may be used or combined with any of the preceding or following aspects, the subject is predicted to not be responsive to the HDAC inhibitor where expression of the one or more miRNAs in the biological sample is reduced as compared to the control sample or is less than the threshold.

[00547] In accordance with another aspect which may be used or combined with any of the preceding or following aspects, the disease or disorder is cancer.

[00548] In accordance with another aspect which may be used or combined with any of the preceding or following aspects, the cancer is selected from the group consisting of gastrointestinal cancer, prostate cancer, ovarian cancer, breast cancer, head and neck cancer, lung cancer, non-small cell lung cancer, cancer of the nervous system, kidney cancer, retina cancer, skin cancer, liver cancer, pancreatic cancer, genital-urinary cancer and bladder cancer.

[00549] In accordance with another aspect which may be used or combined with any of the preceding or following aspects, the step of assaying the test cell for expression of one or more miRNAs is performed by in situ hybridization (ISH), Northern blot or microarray analysis.

[00550] In accordance with another aspect which may be used or combined with any of the preceding or following aspects, the threshold is set at a level of miRNA expression above which a subject is known to respond to treatment with the HDAC inhibitor and below which a subject is known to not respond to treatment with the HDAC inhibitor.

[00551] In accordance with another aspect which may be used or combined with any of the preceding or following aspects,wherein the threshold is set at a level of miRNA expression below which a subject is known to respond to treatment with the HDAC inhibitor and above which a subject is known to not respond to treatment with the HDAC inhibitor.

[00552] In accordance with another aspect which may be used or combined with any of the preceding or following aspects, the threshold is set at a level of miRNA expression above which 50%, 60%, 70%, 80%, 90%, 95%, or greater of subject(s) respond to treatment with the HDAC inhibitor. [00553] In accordance with another aspect which may be used or combined with any of the preceding or following aspects, the threshold is set at a level of miRNA expression above which 50%, 60%, 70%, 80%, 90%, 95% or greater of subject(s) do not respond to treatment with the HDAC inhibitor.

[00554] In accordance with another aspect which may be used or combined with any of the preceding or following aspects, the threshold is set at a level of miRNA expression below which 50%, 60%, 70%, 80%, 90%, 95%, or greater of subject(s) respond to treatment with the HDAC inhibitor.

[00555] In accordance with another aspect which may be used or combined with any of the preceding or following aspects, the threshold is set at a level of miRNA expression below which 50%, 60%, 70%, 80%, 90%, 95%, or greater of subject(s) do not respond to treatment with the HDAC inhibitor.

[00556] In accordance with another aspect which may be used or combined with any of the preceding or following aspects, the subject is a cancer patient.

[00557] In accordance with another aspect which may be used or combined with any of the preceding or following aspects, the method further includes seeking regulatory approval for the histone deacetylase (HDAC) inhibitor.

[00558] In accordance with another aspect which may be used or combined with any of the preceding or following aspects, the clinical trial is a phase I, phase II, phase III or phase IV clinical trial.

[00559] Without limiting the foregoing description, in accordance with another aspect of the subject matter herein, there are provided methods for screening a test cell for sensitivity to a histone deacetylase (HDAC) inhibitor, the method by obtaining a test cell assaying the test cell for expression of one or more miRNAs, and determining if expression of the one or more miRNAs in the test cell is elevated or reduced compared to a control cell or above or below a threshold, wherein the test cell is determined to be sensitive to the HDAC inhibitor where expression of the one or more miRNAs in the test cell is elevated as compared to expression of the one or more miRNAs in the control cell or is above the threshold and wherein the test cell is determined to not be sensitive to the HDAC inhibitor where expression of the one or more miRNAs in the test cell is reduced as compared to expression of the one or more miRNAs in the control cell or is less than the threshold.

[00560] In accordance with another aspect which may be used or combined with any of the preceding or following aspects, the miRNA is one or more of miR-17, miR-20a, miR18a, miR19a, miR-19b or miR92a.

[00561] In accordance with another aspect which may be used or combined with any of the preceding or following aspects, the miRNA is miRNA 17-92. [00562] In accordance with another aspect which may be used or combined with any of the preceding or following aspects, the HDAC inhibitor is a small molecule.

[00563] In accordance with another aspect which may be used or combined with any of the preceding or following aspects, the test cell is from a tumor.

[00564] In accordance with another aspect which may be used or combined with any of the preceding or following aspects, the tumor is a breast or colon tumor.

[00565] In accordance with another aspect which may be used or combined with any of the preceding or following aspects, the test cell is from an aspirate.

[00566] In accordance with another aspect which may be used or combined with any of the preceding or following aspects, the test cell is from a cancer patient.

[00567] In accordance with another aspect which may be used or combined with any of the preceding or following aspects, the step of assaying the test cell for expression of one or more miRNAs is performed by in situ hybridization (ISH), Northern blot or microarray analysis.

[00568] In accordance with another aspect which may be used or combined with any of the preceding or following aspects, the threshold is set at a level of miRNA expression above which a cell is known to be sensitive to treatment with the HDAC inhibitor and below which a cell is known to not be sensitive to treatment with the HDAC inhibitor.

[00569] In accordance with another aspect which may be used or combined with any of the preceding or following aspects, the threshold is set at a level of miRNA expression below which a cell is known to be sensitive to treatment with the HDAC inhibitor and above which a cell is known to not be sensitive to treatment with the HDAC inhibitor.

[00570] In accordance with another aspect which may be used or combined with any of the preceding or following aspects, the threshold is set at a level of miRNA expression above which 50%, 60%, 70%, 80%, 90%, 95%, or greater of cells respond to treatment with the HDAC inhibitor.

[00571] In accordance with another aspect which may be used or combined with any of the preceding or following aspects, the threshold is set at a level of miRNA expression above which 50%, 60%, 70%, 80%, 90%, 95%, or greater of cells do not respond to treatment with the HDAC inhibitor.

[00572] In accordance with another aspect which may be used or combined with any of the preceding or following aspects, the threshold is set at a level of miRNA expression below which 50%, 60%, 70%, 80%, 90%, 95%, or greater of cells do not respond to treatment with the HDAC inhibitor.

[00573] In accordance with another aspect which may be used or combined with any of the preceding or following aspects, the threshold is set at a level of miRNA expression below which 50%, 60%, 70%, 80%, 90%, 95%, or greater of cells respond to treatment with the HDAC inhibitor.

[00574] In accordance with another aspect which may be used or combined with any of the preceding or following aspects, the control cell is the same cell type as the test cell.

[00575] In accordance with another aspect which may be used or combined with any of the preceding or following aspects, the control cell is a different cell type than the test cell.

[00576] Without limiting the foregoing description, in accordance with another aspect of the subject matter herein, there are provided methods for predicting sensitivity of a test cell to a histone deacetylase (HDAC) inhibitor by obtaining a test cell, assaying the test cell for c-myc amplification, determining if c-myc expression and/or c-myc amplification in the test cell in increased or decreased as compared to a control cell or above or below a threshold, and employing the determination of c-myc expression and/or c-myc amplification in the test cell to predict sensitivity of the test cell to the HDAC inhibitor.

[00577] In accordance with another aspect which may be used or combined with any of the preceding or following aspects, the HDAC inhibitor is a small molecule.

[00578] In accordance with another aspect which may be used or combined with any of the preceding or following aspects, the test cell is from a tumor.

[00579] In accordance with another aspect which may be used or combined with any of the preceding or following aspects, the tumor is a breast or colon tumor.

[00580] In accordance with another aspect which may be used or combined with any of the preceding or following aspects, the test cell is from an aspirate.

[00581] In accordance with another aspect which may be used or combined with any of the preceding or following aspects, the test cell is from a cancer patient.

[00582] In accordance with another aspect which may be used or combined with any of the preceding or following aspects, the test cell is predicted to be sensitive to the HDAC inhibitor where c-myc expression and/or c-myc amplification is greater in the test cell as compared to the control cell or is above the threshold.

[00583] In accordance with another aspect which may be used or combined with any of the preceding or following aspects, the test cell is predicted to not be sensitive to the HDAC inhibitor where c-myc expression and/or c-myc amplification is reduced in the test cell as compared to the control cell or is less than the threshold.

[00584] In accordance with another aspect which may be used or combined with any of the preceding or following aspects, the step of assaying the test cell for c-myc expression and/or c-myc amplification is performed by in situ hybridization (ISH), Northern blot or microarray analysis.

[00585] In accordance with another aspect which may be used or combined with any of the preceding or following aspects, the threshold is set at a level of c-myc expression and/or c-myc amplification above which a cell is known to be sensitive to treatment with the HDAC inhibitor and below which a cell is known to not be sensitive to treatment with the HDAC inhibitor.

[00586] In accordance with another aspect which may be used or combined with any of the preceding or following aspects, the threshold is set at a level of c-myc expression and/or c-myc amplification below which a cell is known to be sensitive to treatment with the HDAC inhibitor and above which a cell is known to not be sensitive to treatment with the HDAC inhibitor.

[00587] In accordance with another aspect which may be used or combined with any of the preceding or following aspects, the threshold is set at a level of c-myc expression and/or c-myc amplification above which 50%, 60%, 70%, 80%, 90%, or 95% of cells respond to treatment with a HDAC.

[00588] In accordance with another aspect which may be used or combined with any of the preceding or following aspects, the threshold is set at a level of c-myc expression and/or c-myc amplification above which 50%, 60%, 70%, 80%, 90%, or 95% of cells do not respond to treatment with a HDAC.

[00589] In accordance with another aspect which may be used or combined with any of the preceding or following aspects, the threshold is set at a level of c-myc expression and/or c-myc amplification below which 50%, 60%, 70%, 80%, 90%, or 95% of cells respond to treatment with a HDAC inhibitor.

[00590] In accordance with another aspect which may be used or combined with any of the preceding or following aspects, the threshold is set at a level of c-myc expression and/or c-myc amplification below which 50%, 60%, 70%, 80%, 90%, or 95% of cells do not respond to treatment with a HDAC inhibitor.

[00591] In accordance with another aspect which may be used or combined with any of the preceding or following aspects, the control cell is the same cell type as the test cell.

[00592] In accordance with another aspect which may be used or combined with any of the preceding or following aspects, the control cell is a different cell type than the test cell.

[00593] Without limiting the foregoing description, in accordance with another aspect of the subject matter herein, there are provided methods fori 17. A method for predicting responsiveness of a subject with a disease or disorder to a histone deacetylase (HDAC) inhibitor by obtaining a biological sample from the subject, assaying the biological sample for c-myc expression and/or c-myc amplification, determining if c-myc expression and/or c-myc amplification in the biological sample is increased or decreased as compared to a control sample or above or below a threshold, and employing the determination of c-myc expression and/or c-myc amplification in the biological sample to predict responsiveness of the subject to the HDAC inhibitor.

[00594] In accordance with another aspect which may be used or combined with any of the preceding or following aspects, the HDAC inhibitor is a small molecule.

[00595] In accordance with another aspect which may be used or combined with any of the preceding or following aspects, the biological sample is from a tumor.

[00596] In accordance with another aspect which may be used or combined with any of the preceding or following aspects, the tumor is a breast or colon tumor.

[00597] In accordance with another aspect which may be used or combined with any of the preceding or following aspects, the biological sample is from an aspirate.

[00598] In accordance with another aspect which may be used or combined with any of the preceding or following aspects, the biological sample is from a cancer patient.

[00599] In accordance with another aspect which may be used or combined with any of the preceding or following aspects, the subject is predicted to be responsive to the HDAC inhibitor where c-myc expression and/or c-myc amplification is elevated in the biological sample as compared to the control sample or is greater than the threshold.

[00600] In accordance with another aspect which may be used or combined with any of the preceding or following aspects, the subject is predicted to not be responsive to the HDAC inhibitor where c-myc expression and/or c-myc amplification is reduced in the biological sample as compared to the control sample or is less than the threshold.

[00601] In accordance with another aspect which may be used or combined with any of the preceding or following aspects, the step of assaying the biological sample for c-myc expression and/or c-myc amplification is performed by in situ hybridization (ISH), Northern blot or microarray analysis.

[00602] In accordance with another aspect which may be used or combined with any of the preceding or following aspects, the threshold is set at a level of c-myc expression and/or c-myc amplification above which a subject is known to respond to treatment with the HDAC inhibitor and below which a subject is known to not respond to treatment with the HDAC inhibitor.

[00603] In accordance with another aspect which may be used or combined with any of the preceding or following aspects, the threshold is set at a level of c-myc expression and/or c-myc amplification below which a subject is known to respond to treatment with the HDAC inhibitor and above which a subject is known to not respond to treatment with the HDAC inhibitor.

[00604] In accordance with another aspect which may be used or combined with any of the preceding or following aspects, the threshold is set at a level of c-myc expression and/or c-myc amplification above which 50%, 60%, 70%, 80%, 90%, or 95% of subject(s) respond to treatment with the HDAC inhibitor.

[00605] In accordance with another aspect which may be used or combined with any of the preceding or following aspects, the threshold is set at a level of c-myc expression and/or c-myc amplification above which 50%, 60%, 70%, 80%, 90%, or 95% of subject(s) do not respond to treatment with the HDAC inhibitor.

[00606] In accordance with another aspect which may be used or combined with any of the preceding or following aspects, the threshold is set at a level of c-myc expression and/or c-myc amplification below which 50%, 60%, 70%, 80%, 90%, or 95% of subject(s) respond to treatment with the HDAC inhibitor.

[00607] In accordance with another aspect which may be used or combined with any of the preceding or following aspects, the threshold is set at a level of c-myc expression and/or c-myc amplification below which 50%, 60%, 70%, 80%, 90%, or 95% of subject(s) do not respond to treatment with the HDAC inhibitor.

[00608] In accordance with another aspect which may be used or combined with any of the preceding or following aspects, the disease or disorder is cancer.

[00609] In accordance with another aspect which may be used or combined with any of the preceding or following aspects, the cancer is selected from the group consisting of gastrointestinal, prostate cancer, ovarian cancer, breast cancer, head and neck cancer, lung cancer, non-small cell lung cancer, cancer of the nervous system, kidney cancer, retina cancer, skin cancer, liver cancer, pancreatic cancer, genital-urinary cancer and bladder cancer.

[00610] In accordance with another aspect which may be used or combined with any of the preceding or following aspects, the subject is a cancer patient.

[0061 1] Without limiting the foregoing description, in accordance with another aspect of the subject matter herein, there are provided methods for treating a subject with a disease or disorder by obtaining a biological sample from a subject, assaying the biological sample for c-myc expression and/or c-myc amplification, determining if c-myc expression and/or c- myc amplification in the cell is elevated or reduced compared to a control sample or above or below a threshold, employing the determination of c-myc expression and/or c-myc amplification in the biological sample to predict responsiveness of the subject to the HDAC inhibitor, and administering to the subject a therapeutically effective amount of one or more histone deacetylase (HDAC) inhibitors where the subject is predicted to be responsive to the HDAC inhibitor.

[00612] In accordance with another aspect which may be used or combined with any of the preceding or following aspects, the HDAC inhibitor is a small molecule.

[00613] In accordance with another aspect which may be used or combined with any of the preceding or following aspects, the biological sample is from a tumor.

[00614] In accordance with another aspect which may be used or combined with any of the preceding or following aspects, the tumor is a breast or colon tumor.

[00615] In accordance with another aspect which may be used or combined with any of the preceding or following aspects, the biological sample is from an aspirate.

[00616] In accordance with another aspect which may be used or combined with any of the preceding or following aspects, the biological sample is from a cancer patient.

[00617] In accordance with another aspect which may be used or combined with any of the preceding or following aspects, the subject is predicted to be responsive to the HDAC inhibitor where c-myc expression and/or c-myc amplification is elevated in the biological sample as compared to the control sample or is greater than the threshold.

[00618] In accordance with another aspect which may be used or combined with any of the preceding or following aspects, the subject is predicted to not be responsive to the HDAC inhibitor where c-myc expression and/or c-myc amplification is reduced in the biological sample as compared to the control sample or is less than the threshold.

[00619] In accordance with another aspect which may be used or combined with any of the preceding or following aspects, the disease or disorder is cancer.

[00620] In accordance with another aspect which may be used or combined with any of the preceding or following aspects, the cancer is selected from the group consisting of gastrointestinal cancer, prostate cancer, ovarian cancer, breast cancer, head and neck cancer, lung cancer, non-small cell lung cancer, cancer of the nervous system, kidney cancer, retina cancer, skin cancer, liver cancer, pancreatic cancer, genital-urinary cancer and bladder cancer.

[00621] In accordance with another aspect which may be used or combined with any of the preceding or following aspects, the step of assaying the test cell for c-myc expression and/or c-myc amplification is performed by in situ hybridization (ISH), Northern blot or microarray analysis.

[00622] In accordance with another aspect which may be used or combined with any of the preceding or following aspects, the threshold is set at a level of c-myc expression and/or c-myc amplification above which a subject is known to respond to treatment with the HDAC inhibitor and below which a subject is known to not respond to treatment with the HDAC inhibitor.

[00623] In accordance with another aspect which may be used or combined with any of the preceding or following aspects, the threshold is set at a level of c-myc expression and/or c-myc amplification below which a subject is known to respond to treatment with the HDAC inhibitor and above which a subject is known to not respond to treatment with the HDAC inhibitor.

[00624] In accordance with another aspect which may be used or combined with any of the preceding or following aspects, the threshold is set at a level of c-myc expression and/or c-myc amplification above which 50%, 60%, 70%, 80%, 90%, or 95% of subject(s) respond to treatment with the HDAC inhibitor.

[00625] In accordance with another aspect which may be used or combined with any of the preceding or following aspects, the threshold is set at a level of c-myc expression and/or c-myc amplification above which 50%, 60%, 70%, 80%, 90%, or 95% of subject(s) do not respond to treatment with the HDAC inhibitor.

[00626] In accordance with another aspect which may be used or combined with any of the preceding or following aspects, the threshold is set at a level of c-myc expression and/or c-myc amplification below which 50%, 60%, 70%, 80%, 90%, or 95% of subject(s) respond to treatment with the HDAC inhibitor.

[00627] In accordance with another aspect which may be used or combined with any of the preceding or following aspects, the threshold is set at a level of c-myc expression and/or c-myc amplification below which 50%, 60%, 70%, 80%, 90%, or 95% of subject(s) do not respond to treatment with the HDAC inhibitor.

[00628] In accordance with another aspect which may be used or combined with any of the preceding or following aspects, the subject is a cancer patient.

[00629] In accordance with another aspect which may be used or combined with any of the preceding or following aspects, the therapeutically effective amount of one or more HDAC inhibitors are optionally adapted for a co-treatment with radiotherapy or radio- immunotherapy.

[00630] Without limiting the foregoing description, in accordance with another aspect of the subject matter herein, there are provided methods for selecting subjects for a clinical trial that are responsive to a histone deacetylase (HDAC) inhibitor by obtaining a biological sample from the subjects, assaying the biological samples obtained from the subjects for c- myc expression and/or c-myc amplification, determining if c-myc expression and/or amplification in the biological sample is elevated or reduced compared to a control sample or above or below a threshold, employing the determination of the c-myc expression and/or amplification in the biological sample to predict responsiveness of the subject to the HDAC inhibitor, and selecting subjects for inclusion in a clinical trial that are responsive to the HDAC inhibitor.

[00631] In accordance with another aspect which may be used or combined with any of the preceding or following aspects, the HDAC inhibitor is a small molecule.

[00632] In accordance with another aspect which may be used or combined with any of the preceding or following aspects, the biological sample is from a tumor.

[00633] In accordance with another aspect which may be used or combined with any of the preceding or following aspects, the tumor is a breast or colon tumor.

[00634] In accordance with another aspect which may be used or combined with any of the preceding or following aspects, the biological sample is from an aspirate.

[00635] In accordance with another aspect which may be used or combined with any of the preceding or following aspects, the biological sample is from a cancer patient.

[00636] In accordance with another aspect which may be used or combined with any of the preceding or following aspects, the subject is predicted to be responsive to the HDAC inhibitor where c-myc expression and/or c-myc amplification is elevated in the biological sample as compared to the control sample or is greater than the threshold.

[00637] In accordance with another aspect which may be used or combined with any of the preceding or following aspects, the subject is predicted to not be responsive to the HDAC inhibitor where c-myc expression and/or c-myc amplification is reduced in the biological sample as compared to the control sample or is less than the threshold.

[00638] In accordance with another aspect which may be used or combined with any of the preceding or following aspects, the disease or disorder is cancer.

[00639] In accordance with another aspect which may be used or combined with any of the preceding or following aspects, the cancer is selected from the group consisting of gastrointestinal cancer, prostate cancer, ovarian cancer, breast cancer, head and neck cancer, lung cancer, non-small cell lung cancer, cancer of the nervous system, kidney cancer, retina cancer, skin cancer, liver cancer, pancreatic cancer, genital-urinary cancer and bladder cancer.

[00640] In accordance with another aspect which may be used or combined with any of the preceding or following aspects, the step of assaying the test cell for c-myc expression and/or amplification is performed by in situ hybridization (ISH), Northern blot or microarray analysis.

[00641] In accordance with another aspect which may be used or combined with any of the preceding or following aspects, the threshold is set at a level of c-myc expression and/or c-myc amplification above which a subject is known to respond to treatment with the HDAC inhibitor and below which a subject is known to not respond to treatment with the HDAC inhibitor.

[00642] In accordance with another aspect which may be used or combined with any of the preceding or following aspects, the threshold is set at a level of c-myc expression and/or c-myc amplification above which a subject is known to respond to treatment with the HDAC inhibitor and below which a subject is known to not respond to treatment with the HDAC inhibitor.

[00643] In accordance with another aspect which may be used or combined with any of the preceding or following aspects, the threshold is set at a level of c-myc expression and/or c-myc amplification above which 50%, 60%, 70%, 80%, 90%, or 95% of subject(s) respond to treatment with the HDAC inhibitor.

[00644] In accordance with another aspect which may be used or combined with any of the preceding or following aspects, the threshold is set at a level of c-myc expression and/or c-myc amplification above which 50%, 60%, 70%, 80%, 90%, or 95% of subject(s) do not respond to treatment with the HDAC inhibitor.

[00645] In accordance with another aspect which may be used or combined with any of the preceding or following aspects, the threshold is set at a level of c-myc expression and/or c-myc amplification below which 50%, 60%, 70%, 80%, 90%, or 95% of subject(s) respond to treatment with the HDAC inhibitor.

[00646] In accordance with another aspect which may be used or combined with any of the preceding or following aspects, the threshold is set at a level of c-myc expression and/or c-myc amplification below which 50%, 60%, 70%, 80%, 90%, or 95% of subject(s) do not respond to treatment with the HDAC inhibitor.

[00647] In accordance with another aspect which may be used or combined with any of the preceding or following aspects, the subject is a cancer patient.

[00648] In accordance with another aspect which may be used or combined with any of the preceding or following aspects, the method also includes seeking regulatory approval for the histone deacetylase (HDAC) inhibitor.

[00649] In accordance with another aspect which may be used or combined with any of the preceding or following aspects, the clinical trial is a phase I, phase II, phase III or phase IV clinical trial.

[00650] Without limiting the foregoing description, in accordance with another aspect of the subject matter herein, there are provided methods for screening a test cell for sensitivity to a histone deacetylase (HDAC) inhibitor by obtaining a test cell, assaying the test cell for c-myc expression and/or c-myc amplification; an, determining if c-myc expression and/or c-myc amplification in the test cell is elevated or reduced compared to a control cell or above or below a threshold, wherein the test cell is determined to be sensitive to the HDAC inhibitor where c-myc expression and/or c-myc amplification in the test cell is elevated as compared to c-myc expression and/or c-myc amplification in the control cell or is above the threshold and wherein the test cell is determined to not be sensitive to the HDAC inhibitor where c-myc expression and/or c-myc amplification in the test cell is reduced as compared to c-myc expression and/or c-myc amplification in the control cell or is less than the threshold.

[00651] In accordance with another aspect which may be used or combined with any of the preceding or following aspects, the HDAC inhibitor is a small molecule.

[00652] In accordance with another aspect which may be used or combined with any of the preceding or following aspects, the test cell is from a tumor.

[00653] In accordance with another aspect which may be used or combined with any of the preceding or following aspects, the tumor is a breast or colon tumor.

[00654] In accordance with another aspect which may be used or combined with any of the preceding or following aspects, the test cell is from an aspirate.

[00655] In accordance with another aspect which may be used or combined with any of the preceding or following aspects, the test cell is from a cancer patient.

[00656] In accordance with another aspect which may be used or combined with any of the preceding or following aspects, the step of assaying the test cell for c-myc expression and/or c-myc amplification is performed by in situ hybridization (ISH), Northern blot or microarray analysis.

[00657] In accordance with another aspect which may be used or combined with any of the preceding or following aspects, the threshold is set at a level of c-myc expression and/or c-myc amplification above which a cell is known to be sensitive to treatment with the HDAC inhibitor and below which a cell is known to not be sensitive to treatment with the HDAC inhibitor.

[00658] In accordance with another aspect which may be used or combined with any of the preceding or following aspects, the threshold is set at a level of c-myc expression and/or c-myc amplification below which a cell is known to be sensitive to treatment with the HDAC inhibitor and above which a cell is known to not be sensitive to treatment with the HDAC inhibitor.

[00659] In accordance with another aspect which may be used or combined with any of the preceding or following aspects, the threshold is set at a level of c-myc expression and/or c-myc amplification above which 50%, 60%, 70%, 80%, 90%, 95%, or greater of cells respond to treatment with a HDAC. [00660] In accordance with another aspect which may be used or combined with any of the preceding or following aspects, the threshold is set at a level of c-myc expression and/or c-myc amplification above which 50%, 60%, 70%, 80%, 90%, 95%, or greater of cells do not respond to treatment with a HDAC.

[00661] In accordance with another aspect which may be used or combined with any of the preceding or following aspects, the threshold is set at a level of c-myc expression and/or c-myc amplification below which 50%, 60%, 70%, 80%, 90%, 95%, or greater of cells respond to treatment with a HDAC inhibitor.

[00662] In accordance with another aspect which may be used or combined with any of the preceding or following aspects, the threshold is set at a level of c-myc expression and/or c-myc amplification below which 50%, 60%, 70%, 80%, 90%, 95%, or greater of cells do not respond to treatment with a HDAC inhibitor.

[00663] In accordance with another aspect which may be used or combined with any of the preceding or following aspects, the control cell is the same cell type as the test cell.

[00664] In accordance with another aspect which may be used or combined with any of the preceding or following aspects, the control cell is a different cell type than the test cell.

[00665] Without limiting the foregoing description, in accordance with another aspect of the subject matter herein, there are provided methods for predicting responsiveness of a subject with a disease or disorder to a histone deacetylase (HDAC) inhibitor by obtaining a biological sample from the subject, assaying the biological sample for expression of one or more miRNAs and/or c-myc and/or a c-myc amplification, determining if expression of the one or more miRNAs in the cell is elevated or reduced compared to a control sample or above or below a threshold;, determining if expression of c-myc in the cell is elevated or reduced compared to a control sample or above or below a threshold, determining if c-myc is amplified in the biological sample as compared to a control sample or above or below a threshold, and employing the determination of the expression of the one or more miRNAs and/or c-myc and/or c-myc amplification in the biological sample to predict responsiveness of the subject to the HDAC inhibitor.

[00666] Without limiting the foregoing description, in accordance with another aspect of the subject matter herein, there are provided methods for determining if a subject with a disease or disorder is responding to treatment with a histone deacetylase (HDAC) inhibitor by obtaining a biological sample from the subject, assaying the biological sample for expression of one or more miRNAs, determining if expression of the one or more miRNAs in the biological sample is elevated or reduced compared to a control sample or above or below a threshold, and employing the determination of the expression of the one or more miRNAs in the biological sample to determine if the subject is responding to treatment with the HDAC inhibitor.

[00667] In accordance with another aspect which may be used or combined with any of the preceding or following aspects, the miRNA is one or more of miR-17, miR-20a, miR18a, miR19a, miR-19b or miR92a.

[00668] In accordance with another aspect which may be used or combined with any of the preceding or following aspects, the miRNA is miRNA 17-92.

[00669] In accordance with another aspect which may be used or combined with any of the preceding or following aspects, the HDAC inhibitor is a small molecule.

[00670] In accordance with another aspect which may be used or combined with any of the preceding or following aspects, the biological sample is from a tumor.

[00671] In accordance with another aspect which may be used or combined with any of the preceding or following aspects, the tumor is a breast or colon tumor.

[00672] In accordance with another aspect which may be used or combined with any of the preceding or following aspects, the biological sample is from an aspirate.

[00673] In accordance with another aspect which may be used or combined with any of the preceding or following aspects, the biological sample is from a cancer patient.

[00674] In accordance with another aspect which may be used or combined with any of the preceding or following aspects, the subject is determined to be responding to treatment with the HDAC inhibitor where expression of the one or more miRNAs in the biological sample is elevated as compared to the control sample or is greater than the threshold.

[00675] 199 In accordance with another aspect which may be used or combined with any of the preceding or following aspects, the subject is determined to be responding to treatment with the HDAC inhibitor where expression of the one or more miRNAs in the biological sample is reduced as compared to the control sample or is less than the threshold.

[00676] In accordance with another aspect which may be used or combined with any of the preceding or following aspects, wherein the step of assaying the biological sample for expression of one or more miRNAs is performed by in situ hybridization (ISH), Northern blot or microarray analysis.

[00677] In accordance with another aspect which may be used or combined with any of the preceding or following aspects, the threshold is set at a level of miRNA expression above which a subject is known to respond to treatment with the HDAC inhibitor and below which a subject is known to not respond to treatment with the HDAC inhibitor.

[00678] In accordance with another aspect which may be used or combined with any of the preceding or following aspects, the threshold is set at a level of miRNA expression below which a subject is known to respond to treatment with the HDAC inhibitor and above which a subject is known to not respond to treatment with the HDAC inhibitor.

[00679] In accordance with another aspect which may be used or combined with any of the preceding or following aspects, the threshold is set at a level of miRNA expression above which 50%, 60%, 70%, 80%, 90%, or 95% of subject(s) respond to treatment with the HDAC inhibitor.

[00680] In accordance with another aspect which may be used or combined with any of the preceding or following aspects, the threshold is set at a level of miRNA expression above which 50%, 60%, 70%, 80%, 90%, 95% or greater of subject(s) do not respond to treatment with the HDAC inhibitor.

[00681] In accordance with another aspect which may be used or combined with any of the preceding or following aspects, the threshold is set at a level of miRNA expression below which 50%, 60%, 70%, 80%, 90%, 95%, or greater of subject(s) respond to treatment with the HDAC inhibitor.

[00682] In accordance with another aspect which may be used or combined with any of the preceding or following aspects, the threshold is set at a level of miRNA expression below which 50%, 60%, 70%, 80%, 90%, 95%, or greater of subject(s) do not respond to treatment with the HDAC inhibitor.

[00683] In accordance with another aspect which may be used or combined with any of the preceding or following aspects, the disease or disorder is cancer.

[00684] In accordance with another aspect which may be used or combined with any of the preceding or following aspects, the cancer is selected from the group consisting of gastrointestinal, prostate cancer, ovarian cancer, breast cancer, head and neck cancer, lung cancer, non-small cell lung cancer, cancer of the nervous system, kidney cancer, retina cancer, skin cancer, liver cancer, pancreatic cancer, genital-urinary cancer and bladder cancer.

[00685] In accordance with another aspect which may be used or combined with any of the preceding or following aspects, the subject is a cancer patient.

[00686] Without limiting the foregoing description, in accordance with another aspect of the subject matter herein, there are provided methods for treating a subject with a disease or disorder by administering to the subject a therapeutically effective amount of one or more histone deacetylase (HDAC) inhibitors, obtaining a biological sample from the subject, assaying the biological sample for expression of one or more miRNAs, determining if expression of the one or more miRNAs in the biological sample is elevated or reduced compared to a control sample or above or below a threshold;, employing the determination of the expression of the one or more miRNAs in the biological sample to determine if the subject is responding to treatment with the HDAC inhibitor, and continuing to administer to the subject a therapeutically effective amount of one or more HDAC inhibitors where the subject is determined to be responding to treatment with the HDAC inhibitor or discontinuing treatment of the HDAC inhibitor to the subject where the subject is determined to not be responding to treatment with the HDAC inhibitor.

[00687] In accordance with another aspect which may be used or combined with any of the preceding or following aspects, the miRNA is one or more of miR-17, miR-20a, miR18a, miR19a, miR-19b or miR92a.

[00688] In accordance with another aspect which may be used or combined with any of the preceding or following aspects, the miRNA is miRNA 17-92.

[00689] In accordance with another aspect which may be used or combined with any of the preceding or following aspects, the HDAC inhibitor is a small molecule.

[00690] In accordance with another aspect which may be used or combined with any of the preceding or following aspects, the biological sample is from a tumor.'

[00691] In accordance with another aspect which may be used or combined with any of the preceding or following aspects, the tumor is a breast or colon tumor.

[00692] In accordance with another aspect which may be used or combined with any of the preceding or following aspects, the biological sample is from an aspirate.

[00693] In accordance with another aspect which may be used or combined with any of the preceding or following aspects, the biological sample is from a cancer patient.

[00694] In accordance with another aspect which may be used or combined with any of the preceding or following aspects, the subject is determined to be responding to treatment with the HDAC inhibitor where expression of the one or more miRNAs in the biological sample is elevated as compared to the control sample or is greater than the threshold.

[00695] In accordance with another aspect which may be used or combined with any of the preceding or following aspects, the subject is determined to not be responding to treatment with the HDAC inhibitor where expression of the one or more miRNAs in the biological sample is reduced as compared to the control sample or is less than the threshold.

[00696] In accordance with another aspect which may be used or combined with any of the preceding or following aspects, the disease or disorder is cancer.

[00697] In accordance with another aspect which may be used or combined with any of the preceding or following aspects, the cancer is selected from the group consisting of gastrointestinal cancer, prostate cancer, ovarian cancer, breast cancer, head and neck cancer, lung cancer, non-small cell lung cancer, cancer of the nervous system, kidney cancer, retina cancer, skin cancer, liver cancer, pancreatic cancer, genital-urinary cancer and bladder cancer.

[00698] In accordance with another aspect which may be used or combined with any of the preceding or following aspects, the step of assaying the biological sample for expression of one or more miRNAs is performed by in situ hybridization (ISH), Northern blot or microarray analysis.

[00699] In accordance with another aspect which may be used or combined with any of the preceding or following aspects, the threshold is set at a level of miRNA expression above which a subject is known to respond to treatment with the HDAC inhibitor and below which a subject is known to not respond to treatment with the HDAC inhibitor.

[00700] In accordance with another aspect which may be used or combined with any of the preceding or following aspects, the threshold is set at a level of miRNA expression below which a subject is known to respond to treatment with the HDAC inhibitor and above which a subject is known to not respond to treatment with the HDAC inhibitor.

[00701] In accordance with another aspect which may be used or combined with any of the preceding or following aspects, the threshold is set at a level of miRNA expression above which 50%, 60%, 70%, 80%, 90%, 95%, or greater of subject(s) respond to treatment with the HDAC inhibitor.

[00702] In accordance with another aspect which may be used or combined with any of the preceding or following aspects, the threshold is set at a level of miRNA expression above which 50%, 60%, 70%, 80%, 90%, 95% or greater of subject(s) do not respond to treatment with the HDAC inhibitor.

[00703] In accordance with another aspect which may be used or combined with any of the preceding or following aspects, the threshold is set at a level of miRNA expression below which 50%, 60%, 70%, 80%, 90%, 95%, or greater of subject(s) respond to treatment with the HDAC inhibitor.

[00704] In accordance with another aspect which may be used or combined with any of the preceding or following aspects, the threshold is set at a level of miRNA expression below which 50%, 60%, 70%, 80%, 90%, 95%, or greater of subject(s) do not respond to treatment with the HDAC inhibitor.

[00705] In accordance with another aspect which may be used or combined with any of the preceding or following aspects, the subject is a cancer patient.

[00706] In accordance with another aspect which may be used or combined with any of the preceding or following aspects, the therapeutically effective amount of one or more HDAC inhibitors are optionally adapted for a co-treatment with radiotherapy or radio- immunotherapy. [00707] Without limiting the foregoing description, in accordance with another aspect of the subject matter herein, there are provided methods for selecting subjects for a clinical trial that are determined to be responding to a histone deacetylase (HDAC) inhibitor by administering to the subject a therapeutically effective amount of one or more histone deacetylase (HDAC) inhibitors, obtaining a biological sample from the subject, assaying the biological sample for expression of one or more miRNAs, determining if expression of the one or more miRNAs in the biological sample is elevated or reduced compared to a control sample or above or below a threshold, employing the determination of the expression of the one or more miRNAs in the biological sample to determine if the subject is responding to treatment with the HDAC inhibitor, and selecting subjects for inclusion in the clinical trial that are determined to be responding to treatment with the HDAC inhibitor or selecting subjects for inclusion in the clinical trial that are determined to not be responding to treatment with the HDAC inhibitor.

[00708] In accordance with another aspect which may be used or combined with any of the preceding or following aspects, the miRNA is one or more of miR-17, miR-20a, miR18a, miR19a, miR-19b or miR92a.

[00709] In accordance with another aspect which may be used or combined with any of the preceding or following aspects, the miRNA is miRNA 17-92.

[00710] In accordance with another aspect which may be used or combined with any of the preceding or following aspects, the HDAC inhibitor is a small molecule.

[0071 1] In accordance with another aspect which may be used or combined with any of the preceding or following aspects, the biological sample is from a tumor.

[00712] In accordance with another aspect which may be used or combined with any of the preceding or following aspects, the tumor is a breast or colon tumor.

[00713] In accordance with another aspect which may be used or combined with any of the preceding or following aspects, the biological sample is from an aspirate.

[00714] In accordance with another aspect which may be used or combined with any of the preceding or following aspects, the biological sample is from a cancer patient.

[00715] In accordance with another aspect which may be used or combined with any of the preceding or following aspects, the subject determined to be responding to treatment with the HDAC inhibitor where expression of the one or more miRNAs in the biological sample is elevated as compared to the control sample or is greater than the threshold.

[00716] In accordance with another aspect which may be used or combined with any of the preceding or following aspects, the subject is determined to not be responding to treatment with the HDAC inhibitor where expression of the one or more miRNAs in the biological sample is reduced as compared to the control sample or is less than the threshold. [00717] In accordance with another aspect which may be used or combined with any of the preceding or following aspects, the disease or disorder is cancer.

[00718] In accordance with another aspect which may be used or combined with any of the preceding or following aspects, the cancer is selected from the group consisting of gastrointestinal cancer, prostate cancer, ovarian cancer, breast cancer, head and neck cancer, lung cancer, non-small cell lung cancer, cancer of the nervous system, kidney cancer, retina cancer, skin cancer, liver cancer, pancreatic cancer, genital-urinary cancer and bladder cancer.

[00719] In accordance with another aspect which may be used or combined with any of the preceding or following aspects, the step of assaying the test cell for expression of one or more miRNAs is performed by in situ hybridization (ISH), Northern blot or microarray analysis.

[00720] In accordance with another aspect which may be used or combined with any of the preceding or following aspects, the threshold is set at a level of miRNA expression above which a subject is known to respond to treatment with the HDAC inhibitor and below which a subject is known to not respond to treatment with the HDAC inhibitor.

[00721] In accordance with another aspect which may be used or combined with any of the preceding or following aspects, the threshold is set at a level of miRNA expression below which a subject is known to respond to treatment with the HDAC inhibitor and above which a subject is known to not respond to treatment with the HDAC inhibitor.

[00722] In accordance with another aspect which may be used or combined with any of the preceding or following aspects, the threshold is set at a level of miRNA expression above which 50%, 60%, 70%, 80%, 90%, 95%, or greater of subject(s) respond to treatment with the HDAC inhibitor.

[00723] In accordance with another aspect which may be used or combined with any of the preceding or following aspects, the threshold is set at a level of miRNA expression above which 50%, 60%, 70%, 80%, 90%, 95% or greater of subject(s) do not respond to treatment with the HDAC inhibitor.

[00724] In accordance with another aspect which may be used or combined with any of the preceding or following aspects, the threshold is set at a level of miRNA expression below which 50%, 60%, 70%, 80%, 90%, 95%, or greater of subject(s) respond to treatment with the HDAC inhibitor.

[00725] In accordance with another aspect which may be used or combined with any of the preceding or following aspects, the threshold is set at a level of miRNA expression below which 50%, 60%, 70%, 80%, 90%, 95%, or greater of subject(s) do not respond to treatment with the HDAC inhibitor. [00726] In accordance with another aspect which may be used or combined with any of the preceding or following aspects, the subject is a cancer patient.

[00727] In accordance with another aspect which may be used or combined with any of the preceding or following aspects, the method also includes seeking regulatory approval for the histone deacetylase (HDAC) inhibitor.

[00728] In accordance with another aspect which may be used or combined with any of the preceding or following aspects, the clinical trial is a phase I, phase II, phase III or phase IV clinical trial.

[00729] Without limiting the foregoing description, in accordance with another aspect of the subject matter herein, there are provided methods for determining if a subject with a disease or disorder is responding to treatment with a histone deacetylase (HDAC) inhibitor by obtaining a biological sample from the subject, assaying the biological sample for c-myc expression and/or c-myc amplification, determining if c-myc expression and/or c-myc amplification in the biological sample is increased or decreased as compared to a control sample or above or below a threshold, and employing the determination of c-myc expression and/or c-myc amplification in the biological sample to determine if the subject is responding to treatment with the HDAC inhibitor.

[00730] In accordance with another aspect which may be used or combined with any of the preceding or following aspects, the HDAC inhibitor is a small molecule.

[00731] In accordance with another aspect which may be used or combined with any of the preceding or following aspects, the biological sample is from a tumor.

[00732] In accordance with another aspect which may be used or combined with any of the preceding or following aspects, the tumor is from a breast or colon tumor.

[00733] In accordance with another aspect which may be used or combined with any of the preceding or following aspects, the biological sample is from an aspirate.

[00734] In accordance with another aspect which may be used or combined with any of the preceding or following aspects, the biological sample is from a cancer patient.

[00735] In accordance with another aspect which may be used or combined with any of the preceding or following aspects, the subject is predicted to be responsive to the HDAC inhibitor where c-myc expression and/or c-myc amplification is elevated in the biological sample as compared to the control sample or is greater than the threshold.

[00736] In accordance with another aspect which may be used or combined with any of the preceding or following aspects, the subject is predicted to not be responsive to the HDAC inhibitor where c-myc expression and/or c-myc amplification is reduced in the biological sample as compared to the control sample or is less than the threshold. [00737] In accordance with another aspect which may be used or combined with any of the preceding or following aspects, the step of assaying the biological sample for c-myc expression and/or c-myc amplification is performed by in situ hybridization (ISH), Northern blot or microarray analysis.

[00738] In accordance with another aspect which may be used or combined with any of the preceding or following aspects, the threshold is set at a level of c-myc expression and/or c-myc amplification above which a subject is known to respond to treatment with the HDAC inhibitor and below which a subject is known to not respond to treatment with the HDAC inhibitor.

[00739] In accordance with another aspect which may be used or combined with any of the preceding or following aspects, the threshold is set at a level of c-myc expression and/or c-myc amplification below which a subject is known to respond to treatment with the HDAC inhibitor and above which a subject is known to not respond to treatment with the HDAC inhibitor.

[00740] In accordance with another aspect which may be used or combined with any of the preceding or following aspects, the threshold is set at a level of c-myc expression and/or c-myc amplification above which 50%, 60%, 70%, 80%, 90%, or 95% of subject(s) respond to treatment with the HDAC inhibitor.

[00741] In accordance with another aspect which may be used or combined with any of the preceding or following aspects, the threshold is set at a level of c-myc expression and/or c-myc amplification above which 50%, 60%, 70%, 80%, 90%, or 95% of subject(s) do not respond to treatment with the HDAC inhibitor.

[00742] In accordance with another aspect which may be used or combined with any of the preceding or following aspects, the threshold is set at a level of c-myc expression and/or c-myc amplification below which 50%, 60%, 70%, 80%, 90%, or 95% of subject(s) respond to treatment with the HDAC inhibitor.

[00743] In accordance with another aspect which may be used or combined with any of the preceding or following aspects, the threshold is set at a level of c-myc expression and/or c-myc amplification below which 50%, 60%, 70%, 80%, 90%, or 95% of subject(s) do not respond to treatment with the HDAC inhibitor.

[00744] In accordance with another aspect which may be used or combined with any of the preceding or following aspects, the disease or disorder is cancer.

[00745] In accordance with another aspect which may be used or combined with any of the preceding or following aspects, the cancer is selected from the group consisting of gastrointestinal, prostate cancer, ovarian cancer, breast cancer, head and neck cancer, lung cancer, non-small cell lung cancer, cancer of the nervous system, kidney cancer, retina cancer, skin cancer, liver cancer, pancreatic cancer, genital-urinary cancer and bladder cancer.

[00746] In accordance with another aspect which may be used or combined with any of the preceding or following aspects, the subject is a cancer patient.

[00747] Without limiting the foregoing description, in accordance with another aspect of the subject matter herein, there are provided methods for treating a subject with a disease or disorder by administering to the subject a therapeutically effective amount of one or more histone deacetylase (HDAC) inhibitors, obtaining a biological sample from a subject, assaying the biological sample for c-myc expression and/or c-myc amplification, determining if c-myc expression and/or c-myc amplification in the cell is elevated or reduced compared to a control sample or above or below a threshold;, employing the determination of c-myc expression and/or c-myc amplification in the biological sample to determine if the subject is responding to treatment with the HDAC inhibitor, and continuing to administer to the subject a therapeutically effective amount of one or more HDAC inhibitors where the subject is determined to be responding to treatment with the HDAC inhibitor or discontinuing treatment of the HDAC inhibitor to the subject where the subject is determined to not be responding to treatment with the HDAC inhibitor.

[00748] In accordance with another aspect which may be used or combined with any of the preceding or following aspects, the HDAC inhibitor is a small molecule.

[00749] In accordance with another aspect which may be used or combined with any of the preceding or following aspects, the biological sample is from a tumor.

[00750] In accordance with another aspect which may be used or combined with any of the preceding or following aspects, the tumor is from a breast or colon tumor.

[00751] In accordance with another aspect which may be used or combined with any of the preceding or following aspects, the biological sample is from an aspirate.

[00752] In accordance with another aspect which may be used or combined with any of the preceding or following aspects, the biological sample is from a cancer patient.

[00753] In accordance with another aspect which may be used or combined with any of the preceding or following aspects, the subject is predicted to be responsive to the HDAC inhibitor where c-myc expression and/or c-myc amplification is elevated in the biological sample as compared to the control sample or is greater than the threshold.

[00754] In accordance with another aspect which may be used or combined with any of the preceding or following aspects, the subject is predicted to not be responsive to the HDAC inhibitor where c-myc expression and/or c-myc amplification is reduced in the biological sample as compared to the control sample or is less than the threshold. [00755] In accordance with another aspect which may be used or combined with any of the preceding or following aspects, the disease or disorder is cancer.

[00756] In accordance with another aspect which may be used or combined with any of the preceding or following aspects, the cancer is selected from the group consisting of gastrointestinal cancer, prostate cancer, ovarian cancer, breast cancer, head and neck cancer, lung cancer, non-small cell lung cancer, cancer of the nervous system, kidney cancer, retina cancer, skin cancer, liver cancer, pancreatic cancer, genital-urinary cancer and bladder cancer.

[00757] In accordance with another aspect which may be used or combined with any of the preceding or following aspects, the step of assaying the test cell for c-myc expression and/or c-myc amplification is performed by in situ hybridization (ISH), Northern blot or microarray analysis.

[00758] In accordance with another aspect which may be used or combined with any of the preceding or following aspects, the threshold is set at a level of c-myc expression and/or c-myc amplification above which a subject is known to respond to treatment with the HDAC inhibitor and below which a subject is known to not respond to treatment with the HDAC inhibitor.

[00759] In accordance with another aspect which may be used or combined with any of the preceding or following aspects, the threshold is set at a level of c-myc expression and/or c-myc amplification below which a subject is known to respond to treatment with the HDAC inhibitor and above which a subject is known to not respond to treatment with the HDAC inhibitor.

[00760] In accordance with another aspect which may be used or combined with any of the preceding or following aspects, the threshold is set at a level of c-myc expression and/or c-myc amplification above which 50%, 60%, 70%, 80%, 90%, or 95% of subject(s) respond to treatment with the HDAC inhibitor.

[00761] In accordance with another aspect which may be used or combined with any of the preceding or following aspects, the threshold is set at a level of c-myc expression and/or c-myc amplification above which 50%, 60%, 70%, 80%, 90%, or 95% of subject(s) do not respond to treatment with the HDAC inhibitor.

[00762] In accordance with another aspect which may be used or combined with any of the preceding or following aspects, the threshold is set at a level of c-myc expression and/or c-myc amplification below which 50%, 60%, 70%, 80%, 90%, or 95% of subject(s) respond to treatment with the HDAC inhibitor.

[00763] In accordance with another aspect which may be used or combined with any of the preceding or following aspects, the threshold is set at a level of c-myc expression and/or c-myc amplification below which 50%, 60%, 70%, 80%, 90%, or 95% of subject(s) do not respond to treatment with the HDAC inhibitor.

[00764] In accordance with another aspect which may be used or combined with any of the preceding or following aspects, the subject is a cancer patient.

[00765] In accordance with another aspect which may be used or combined with any of the preceding or following aspects, the therapeutically effective amount of one or more HDAC inhibitors are optionally adapted for a co-treatment with radiotherapy or radio- immunotherapy.

[00766] Without limiting the foregoing description, in accordance with another aspect of the subject matter herein, there are provided methods for selecting subjects for a clinical trial that are determined to be responding to a histone deacetylase (HDAC) inhibitor by administering to the subject a therapeutically effective amount of one or more histone deacetylase (HDAC) inhibitors, obtaining a biological sample from the subjects, assaying the biological samples obtained from the subjects for c-myc expression and/or c-myc amplification, determining if c-myc expression and/or amplification in the biological sample is elevated or reduced compared to a control sample or above or below a threshold, employing the determination of the c-myc expression and/or amplification in the biological sample to determine if the subject is responding to treatment with the HDAC inhibitor, and selecting subjects for inclusion in the clinical trial that are determined to be responding to treatment with the HDAC inhibitor or selecting subjects for inclusion in the clinical trial that are determined to not be responding to treatment with the HDAC inhibitor.

[00767] In accordance with another aspect which may be used or combined with any of the preceding or following aspects, the HDAC inhibitor is a small molecule.

[00768] In accordance with another aspect which may be used or combined with any of the preceding or following aspects, the biological sample is from a tumor.

[00769] In accordance with another aspect which may be used or combined with any of the preceding or following aspects, the tumor is from a breast or colon tumor.

[00770] In accordance with another aspect which may be used or combined with any of the preceding or following aspects, the biological sample is from an aspirate.

[00771] In accordance with another aspect which may be used or combined with any of the preceding or following aspects, the biological sample is from a cancer patient.

[00772] In accordance with another aspect which may be used or combined with any of the preceding or following aspects, the subject is predicted to be responsive to the HDAC inhibitor where c-myc expression and/or c-myc amplification is elevated in the biological sample as compared to the control sample or is greater than the threshold. [00773] In accordance with another aspect which may be used or combined with any of the preceding or following aspects, the subject is predicted to not be responsive to the HDAC inhibitor where c-myc expression and/or c-myc amplification is reduced in the biological sample as compared to the control sample or is less than the threshold.

[00774] In accordance with another aspect which may be used or combined with any of the preceding or following aspects, the disease or disorder is cancer.

[00775] In accordance with another aspect which may be used or combined with any of the preceding or following aspects, the cancer is selected from the group consisting of gastrointestinal cancer, prostate cancer, ovarian cancer, breast cancer, head and neck cancer, lung cancer, non-small cell lung cancer, cancer of the nervous system, kidney cancer, retina cancer, skin cancer, liver cancer, pancreatic cancer, genital-urinary cancer and bladder cancer.

[00776] In accordance with another aspect which may be used or combined with any of the preceding or following aspects, the step of assaying the test cell for c-myc expression and/or amplification is performed by in situ hybridization (ISH), Northern blot or microarray analysis.

[00777] In accordance with another aspect which may be used or combined with any of the preceding or following aspects, the threshold is set at a level of c-myc expression and/or c-myc amplification above which a subject is known to respond to treatment with the HDAC inhibitor and below which a subject is known to not respond to treatment with the HDAC inhibitor.

[00778] In accordance with another aspect which may be used or combined with any of the preceding or following aspects, the threshold is set at a level of c-myc expression and/or c-myc amplification below which a subject is known to respond to treatment with the HDAC inhibitor and above which a subject is known to not respond to treatment with the HDAC inhibitor.

[00779] In accordance with another aspect which may be used or combined with any of the preceding or following aspects, the threshold is set at a level of c-myc expression and/or c-myc amplification above which 50%, 60%, 70%, 80%, 90%, or 95% of subject(s) respond to treatment with the HDAC inhibitor.

[00780] In accordance with another aspect which may be used or combined with any of the preceding or following aspects, the threshold is set at a level of c-myc expression and/or c-myc amplification above which 50%, 60%, 70%, 80%, 90%, or 95% of subject(s) do not respond to treatment with the HDAC inhibitor.

[00781] In accordance with another aspect which may be used or combined with any of the preceding or following aspects, the threshold is set at a level of c-myc expression and/or c-myc amplification below which 50%, 60%, 70%, 80%, 90%, or 95% of subject(s) respond to treatment with the HDAC inhibitor.

[00782] In accordance with another aspect which may be used or combined with any of the preceding or following aspects, the threshold is set at a level of c-myc expression and/or c-myc amplification below which 50%, 60%, 70%, 80%, 90%, or 95% of subject(s) do not respond to treatment with the HDAC inhibitor.

[00783] In accordance with another aspect which may be used or combined with any of the preceding or following aspects, the subject is a cancer patient.

[00784] In accordance with another aspect which may be used or combined with any of the preceding or following aspects, the method includes seeking regulatory approval for the histone deacetylase (HDAC) inhibitor.

[00785] In accordance with another aspect which may be used or combined with any of the preceding or following aspects, the clinical trial is a phase I, phase II, phase III or phase IV clinical trial.

[00786] Unless otherwise indicated, all numbers expressing quantities of ingredients, properties such as molecular weight, reaction conditions, and so forth used in the specification and claims are to be understood as being modified in all instances by the term "about." Accordingly, unless indicated to the contrary, the numerical parameters set forth in the specification and attached claims are approximations that may vary depending upon the desired properties sought to be obtained by the present disclosure. At the very least, and not as an attempt to limit the application of the doctrine of equivalents to the scope of the claims, each numerical parameter should at least be construed in light of the number of reported significant digits and by applying ordinary rounding techniques.

[00787] Notwithstanding that the numerical ranges and parameters setting forth the broad scope of the disclosure are approximations, the numerical values set forth in the specific examples are reported as precisely as possible. Any numerical value, however, inherently contains certain errors necessarily resulting from the standard deviation found in their respective testing measurements.

[00788] The terms "a," "an," "the" and similar referents used in the context of describing the disclosure (especially in the context of the following claims) are to be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context. Recitation of ranges of values herein is merely intended to serve as a shorthand method of referring individually to each separate value falling within the range. Unless otherwise indicated herein, each individual value is incorporated into the specification as if it were individually recited herein. All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples, or exemplary language (e.g., "such as") provided herein is intended merely to better illuminate the disclosure and does not pose a limitation on the scope of the disclosure otherwise claimed. No language in the specification should be construed as indicating any non-claimed element essential to the practice of the disclosure.

[00789] Groupings of alternative elements or embodiments of the disclosure disclosed herein are not to be construed as limitations. Each group member can be referred to and claimed individually or in any combination with other members of the group or other elements found herein. It is anticipated that one or more members of a group can be included in, or deleted from, a group for reasons of convenience and/or patentability. When any such inclusion or deletion occurs, the specification is deemed to contain the group as modified thus fulfilling the written description of all Markush groups used in the appended claims.

[00790] Certain embodiments of this disclosure are described herein, including the best mode known to the inventors for carrying out the disclosure. Of course, variations on these described embodiments will become apparent to those of ordinary skill in the art upon reading the foregoing description. The inventor expects skilled artisans to employ such variations as appropriate, and the inventors intend for the disclosure to be practiced otherwise than specifically described herein. Accordingly, this disclosure includes all modifications and equivalents of the subject matter recited in the claims appended hereto as permitted by applicable law. Moreover, any combination of the above-described elements in all possible variations thereof is encompassed by the disclosure unless otherwise indicated herein or otherwise clearly contradicted by context.

[00791] Specific embodiments disclosed herein can be further limited in the claims using consisting of or and consisting essentially of language. When used in the claims, whether as filed or added per amendment, the transition term "consisting of" excludes any element, step, or ingredient not specified in the claims. The transition term "consisting essentially of" limits the scope of a claim to the specified materials or steps and those that do not materially affect the basic and novel characteristic(s). Embodiments of the disclosure so claimed are inherently or expressly described and enabled herein.

[00792] It is to be understood that the embodiments of the disclosure disclosed herein are illustrative of the principles of the present disclosure. Other modifications that can be employed are within the scope of the disclosure. Thus, by way of example, but not of limitation, alternative configurations of the present disclosure can be utilized in accordance with the teachings herein. Accordingly, the present disclosure is not limited to that precisely as shown and described. [00793] While the present disclosure has been described and illustrated herein by references to various specific materials, procedures and examples, it is understood that the disclosure is not restricted to the particular combinations of materials and procedures selected for that purpose. Numerous variations of such details can be implied as will be appreciated by those skilled in the art. It is intended that the specification and examples be considered as exemplary, only, with the true scope and spirit of the disclosure being indicated by the following claims. All references, patents, and patent applications referred to in this application are herein incorporated by reference in their entirety.

Claims

1. 1. A method for predicting responsiveness of a subject with a disease or disorder to

treatment with a histone deacetylase (HDAC) inhibitor, the method comprising:

a. obtaining a biological sample from the subject;

b. assaying the biological sample for expression of one or more miRNAs, c-myc expression, and/or c-myc amplification;

c. determining if expression of the one or more miRNAs, c-myc expression, and/or c-myc amplification in the biological sample is elevated or reduced compared to a control sample or above or below a threshold; and

d. employing the determination of the expression of the one or more miRNAs, c- myc expression, and/or c-myc amplification in the biological sample to predict responsiveness of the subject to the HDAC inhibitor.

2. The method of claim 1 , wherein the miRNA is one or more of miR-17, miR-20a, miR18a, miR19a, miR-19b or miR92a.

3. The method of claim 1 , wherein the miRNA is miRNA 17-92.

4. The method of claim 1 , wherein the HDAC inhibitor is a small molecule.

5. The method of claim 1 , wherein the biological sample is from a tumor.

6. The method of claim 5, wherein the tumor is a breast or colon tumor.

7. The method of claim 1 , wherein the biological sample is from an aspirate.

8. The method of claim 1 , wherein the biological sample is from a cancer patient.

9. The method of claim 1 , wherein the subject is predicted to be responsive to the HDAC inhibitor where expression of the one or more miRNAs, c-myc expression, and/or c-myc amplification in the biological sample is elevated as compared to the control sample or is greater than the threshold.

10. The method of claim 1 , wherein the subject is predicted to not be responsive to the HDAC inhibitor where expression of the one or more miRNAs, c-myc expression, and/or c-myc amplification in the biological sample is reduced as compared to the control sample or is less than the threshold.

11. The method of claim 1 , wherein the step of assaying the biological sample for expression of one or more miRNAs, c-myc expression, and/or c-myc amplification is performed by in situ hybridization (ISH), Northern blot or microarray analysis.

12. The method of claim 1 , wherein the threshold is set at a level of miRNA expression or c- myc expression and/or c-myc amplification above which a subject is known to respond to treatment with the HDAC inhibitor and below which a subject is known to not respond to treatment with the HDAC inhibitor.

13. The method of claim 1 , wherein the threshold is set at a level of miRNA expression or c- myc expression and/or c-myc amplification below which a subject is known to respond to treatment with the HDAC inhibitor and above which a subject is known to not respond to treatment with the HDAC inhibitor.

14. The method of claim 12, wherein the threshold is set at a level of miRNA expression or c-myc expression and/or c-myc amplification above which 50%, 60%, 70%, 80%, 90%, or 95% of subject(s) respond to treatment with the HDAC inhibitor.

15. The method of claim 13, wherein the threshold is set at a level of miRNA expression or c-myc expression and/or c-myc amplification above which 50%, 60%, 70%, 80%, 90%, 95% or greater of subject(s) do not respond to treatment with the HDAC inhibitor.

16. The method of claim 12, wherein the threshold is set at a level of miRNA expression or c-myc expression and/or c-myc amplification below which 50%, 60%, 70%, 80%, 90%, 95%, or greater of subject(s) respond to treatment with the HDAC inhibitor.

17. The method of claim 13, wherein the threshold is set at a level of miRNA expression or c-myc expression and/or c-myc amplification below which 50%, 60%, 70%, 80%, 90%, 95%, or greater of subject(s) do not respond to treatment with the HDAC inhibitor.

18. The method of claim 1 , wherein the disease or disorder is cancer.

19. The method of claim 18, wherein the cancer is selected from the group consisting of gastrointestinal, prostate cancer, ovarian cancer, breast cancer, head and neck cancer, lung cancer, non-small cell lung cancer, cancer of the nervous system, kidney cancer, retina cancer, skin cancer, liver cancer, pancreatic cancer, genital-urinary cancer and bladder cancer.

20. The method of claim 1 , wherein the subject is a cancer patient.

21. A method for treating a subject with a disease or disorder, the method comprising:

a. obtaining a biological sample from a subject;

c. determining if expression of the one or more miRNAs, c-myc expression, and/or c-myc amplification in the biological sample is elevated or reduced compared to a control sample or above or below a threshold;

d. employing the determination of the expression of the one or more miRNAs, c- myc expression, and/or c-myc amplification in the biological sample to predict responsiveness of the subject to the HDAC inhibitor; and

e. administering to the subject a therapeutically effective amount of one or more histone deacetylase (HDAC) inhibitors where the subject is predicted to be responsive to the HDAC inhibitor.

22. The method of claim 21 , wherein the miRNA is one or more of miR-17, miR-20a, miR18a, miR19a, miR-19b or miR92a.

23. The method of claim 21 , wherein the miRNA is miRNA 17-92.

24. The method of claim 21 , wherein the subject is predicted to be responsive to the HDAC inhibitor where expression of the one or more miRNAs, c-myc expression, and/or c-myc amplification in the biological sample is elevated as compared to the control sample or is greater than the threshold.

25. The method of claim 21 , wherein the subject is predicted to not be responsive to the HDAC inhibitor where expression of the one or more miRNAs, c-myc expression, and/or c-myc amplification in the biological sample is reduced as compared to the control sample or is less than the threshold.

26. The method of claim 21 , wherein the disease or disorder is cancer.

27. The method of claim 26, wherein the cancer is selected from the group consisting of gastrointestinal cancer, prostate cancer, ovarian cancer, breast cancer, head and neck cancer, lung cancer, non-small cell lung cancer, cancer of the nervous system, kidney cancer, retina cancer, skin cancer, liver cancer, pancreatic cancer, genital-urinary cancer and bladder cancer.

28. The method of claim 21 , wherein the step of assaying the biological sample for expression of one or more miRNAs, c-myc expression, and/or c-myc amplification is performed by in situ hybridization (ISH), Northern blot or microarray analysis.

29. The method of claim 21 , wherein the threshold is set at a level of miRNA expression or c-myc expression and/or c-myc amplification above which a subject is known to respond to treatment with the HDAC inhibitor and below which a subject is known to not respond to treatment with the HDAC inhibitor.

30. The method of claim 21 , wherein the threshold is set at a level of miRNA or c-myc expression and/or c-myc amplification below which a subject is known to respond to treatment with the HDAC inhibitor and above which a subject is known to not respond to treatment with the HDAC inhibitor.

31. The method of claim 29, wherein the threshold is set at a level of miRNA expression or c-myc expression and/or c-myc amplification above which 50%, 60%, 70%, 80%, 90%, 95%, or greater of subject(s) respond to treatment with the HDAC inhibitor.

32. The method of claim 30, wherein the threshold is set at a level of miRNA expression or c-myc expression and/or c-myc amplification above which 50%, 60%, 70%, 80%, 90%, 95% or greater of subject(s) do not respond to treatment with the HDAC inhibitor.

33. The method of claim 30, wherein the threshold is set at a level of miRNA expression or c-myc expression and/or c-myc amplification below which 50%, 60%, 70%, 80%, 90%, 95%, or greater of subject(s) respond to treatment with the HDAC inhibitor.

34. The method of claim 29, wherein the threshold is set at a level of miRNA expression or c-myc expression and/or c-myc amplification below which 50%, 60%, 70%, 80%, 90%, 95%, or greater of subject(s) do not respond to treatment with the HDAC inhibitor.

35. The method of claim 21 , wherein the subject is a cancer patient.

36. The method of claim 21 , wherein the therapeutically effective amount of one or more HDAC inhibitors are optionally adapted for a co-treatment with radiotherapy or radio- immunotherapy.

37. A method for selecting subjects for a clinical trial that are responsive to treatment with a histone deacetylase (HDAC) inhibitor, the method comprising:

a. obtaining a biological sample from the subjects;

b. assaying the biological samples obtained from the subjects for expression of one or more miRNAs and/or c-myc expression and/or c-myc amplification; c. determining if expression of the one or more miRNAs and/or c-myc expression and/or c-myc amplification in the biological sample is elevated or reduced compared to a control sample or above or below a threshold;

d. employing the determination of the expression of the one or more miRNAs and/or c-myc expression and/or c-myc amplification in the biological sample to predict responsiveness of the subject to the HDAC inhibitor; and

e. selecting subjects for inclusion in a clinical trial that are responsive to the HDAC inhibitor.

38. The method of claim 37, wherein the miRNA is one or more of miR-17, miR-20a, miR18a, miR19a, miR-19b or miR92a.

39. The method of claim 37, wherein the miRNA is miRNA 17-92.

40. The method of claim 37, wherein the subject is predicted to be responsive to the HDAC inhibitor where expression of the one or more miRNAs and/or c-myc expression and/or c-myc amplification in the biological sample is elevated as compared to the control sample or is greater than the threshold.

41. The method of claim 37, wherein the subject is predicted to not be responsive to the HDAC inhibitor where expression of the one or more miRNAs and/or c-myc expression and/or c-myc amplification in the biological sample is reduced as compared to the control sample or is less than the threshold.

42. The method of claim 37, wherein the disease or disorder is cancer.

43. The method of claim 42, wherein the cancer is selected from the group consisting of gastrointestinal cancer, prostate cancer, ovarian cancer, breast cancer, head and neck cancer, lung cancer, non-small cell lung cancer, cancer of the nervous system, kidney cancer, retina cancer, skin cancer, liver cancer, pancreatic cancer, genital-urinary cancer and bladder cancer.

44. The method of claim 37, wherein the step of assaying the test cell for expression of one or more miRNAs is performed by in situ hybridization (ISH), Northern blot or microarray analysis.

45. The method of claim 37, wherein the threshold is set at a level of miRNA expression or c-myc expression and/or c-myc amplification above which a subject is known to respond to treatment with the HDAC inhibitor and below which a subject is known to not respond to treatment with the HDAC inhibitor.

46. The method of claim 37, wherein the threshold is set at a level of miRNA expression or c-myc expression and/or c-myc amplification below which a subject is known to respond to treatment with the HDAC inhibitor and above which a subject is known to not respond to treatment with the HDAC inhibitor.

47. The method of claim 45, wherein the threshold is set at a level of miRNA expression or c-myc expression and/or c-myc amplification above which 50%, 60%, 70%, 80%, 90%, 95%, or greater of subject(s) respond to treatment with the HDAC inhibitor.

48. The method of claim 46, wherein the threshold is set at a level of miRNA expression or c-myc expression and/or c-myc amplification above which 50%, 60%, 70%, 80%, 90%, 95% or greater of subject(s) do not respond to treatment with the HDAC inhibitor.

49. The method of claim 45, wherein the threshold is set at a level of miRNA expression or c-myc expression and/or c-myc amplification below which 50%, 60%, 70%, 80%, 90%, 95%, or greater of subject(s) respond to treatment with the HDAC inhibitor.

50. The method of claim 46, wherein the threshold is set at a level of miRNA expression or c-myc expression and/or c-myc amplification below which 50%, 60%, 70%, 80%, 90%, 95%, or greater of subject(s) do not respond to treatment with the HDAC inhibitor.

51. The method of claim 37, wherein the subject is a cancer patient.

52. The method of claim 37 further comprising seeking regulatory approval for the histone deacetylase (HDAC) inhibitor.

53. The method of claim 37, wherein the clinical trial is a phase I, phase II, phase III or phase IV clinical trial.

54. A method for determining if a subject with a disease or disorder is responding to treatment with a histone deacetylase (HDAC) inhibitor, the method comprising:

a. obtaining a biological sample from the subject;

b. assaying the biological sample for expression of one or more miRNAs;

c. determining if expression of the one or more miRNAs in the biological sample is elevated or reduced compared to a control sample or above or below a threshold; and d. employing the determination of the expression of the one or more miRNAs in the biological sample to determine if the subject is responding to treatment with the HDAC inhibitor.

55. The method of claim 54, wherein the miRNA is one or more of miR-17, miR-20a, miR18a, miR19a, miR-19b or miR92a.

56. The method of claim 54, wherein the miRNA is miRNA 17-92.

57. The method of claim 54, wherein the subject is determined to be responding to treatment with the HDAC inhibitor where expression of the one or more miRNAs in the biological sample is elevated as compared to the control sample or is greater than the threshold.

58. The method of claim 57, wherein the subject is determined to be responding to treatment with the HDAC inhibitor where expression of the one or more miRNAs in the biological sample is reduced as compared to the control sample or is less than the threshold.

59. The method of claim 54, wherein the threshold is set at a level of miRNA expression above which a subject is known to respond to treatment with the HDAC inhibitor and below which a subject is known to not respond to treatment with the HDAC inhibitor.

60. The method of claim 54, wherein the threshold is set at a level of miRNA expression below which a subject is known to respond to treatment with the HDAC inhibitor and above which a subject is known to not respond to treatment with the HDAC inhibitor.

61. The method of claim 59, wherein the threshold is set at a level of miRNA expression above which 50%, 60%, 70%, 80%, 90%, or 95% of subject(s) respond to treatment with the HDAC inhibitor.

62. The method of claim 60, wherein the threshold is set at a level of miRNA expression above which 50%, 60%, 70%, 80%, 90%, 95% or greater of subject(s) do not respond to treatment with the HDAC inhibitor.

63. The method of claim 59, wherein the threshold is set at a level of miRNA expression below which 50%, 60%, 70%, 80%, 90%, 95%, or greater of subject(s) respond to treatment with the HDAC inhibitor.

64. The method of claim 60, wherein the threshold is set at a level of miRNA expression below which 50%, 60%, 70%, 80%, 90%, 95%, or greater of subject(s) do not respond to treatment with the HDAC inhibitor.