WO2016166600A1

WO2016166600A1 - Delivery of microrna using mesenchymal stem cell microparticles

Info

Publication number: WO2016166600A1
Application number: PCT/IB2016/000563
Authority: WO
Inventors: Agamemnon Epenetos; Marianna PROKOPI
Original assignee: TROJANTEC TECHNOLOGIES Ltd
Current assignee: TROJANTEC TECHNOLOGIES Ltd
Priority date: 2015-04-15
Filing date: 2016-04-15
Publication date: 2016-10-20
Anticipated expiration: 2017-10-15

Abstract

MIRNAs have been implicated in the development of some if not all cancer types and have been identified as attractive targets for therapy. However, systemic delivery of miRNAs faces its own set of limitations because of degradation by RNases and filtration and excretion by the kidneys. In this work we propose a new class of therapeutic agents, based on microparticles (MPs) derived from mesenchymal stem cells (MSCs) that can selectively target tumors in vivo, containing and delivering miRNAs that affect the action of genes associated with cancer growth, neovascularization and metastasis applicable to both local and systemic administration.

Description

DELIVERY OF MICRORNA USING MESENCHYMAL STEM CELL

MICROPARTICLES

RELATED APPLICATIONS

[0001] This application claims benefit of U.S. Provisional Application Serial No. 62/148,076 filed on April 15, 2015, the contents of which are incorporated herein by reference.

FIELD OF THE INVENTION

[0002] The present invention relates generally to the treatment of cancer and more specifically to the use of microparticles containing microRNA for the treatment of cancer.

BACKGROUND INFORMATION

[0003] Non-coding RNA (ncRNA) is an RNA molecule that is not translated into a protein. Less-frequently used synonyms are non-protein-coding RNA (npcRNA), non- messenger RNA (nmRNA), functional RNA (fRNA) or simply RNA. The DNA sequence from which a functional non-coding RNA is transcribed is often called an RNA gene. Non- coding RNA genes include highly abundant and functionally important RNAs such as transfer RNAs (tRNAs) and ribosomal RNAs (rRNAs), as well as RNAs such as snoRNAs, microRNAs, siRNAs, snRNAs, exRNAs, piRNAs and scaRNAs and the long ncRNAs that include examples such as Xist and HOTAIR. The number of ncRNAs encoded within the human genome is unknown; however, recent transcriptomic and bioinformatic studies suggest the existence of thousands of ncRNAs. Since many of the newly identified ncRNAs have not been validated for their function, it is possible that many are non-functional. It is also likely that many ncRNAs are non functional, and are the product of spurious transcription. Non-coding RNA have roles in several biological functions RNA splicing, DNA replication, gene regulation, genome defense, chromosome structure and also have a role in several diseases and disorders such as cancer, Autism, Alzheimer's disease and hearing loss. Cancer is one of the leading diseases the human population is facing. Many types of cancer are still impossible to be cured with conventional therapies/drugs. This poor outcome of cancer therapy relates in part to insufficient drug or gene delivery to tumor sites; therefore, there is an urgent need to propose novel strategies for tumor targeting. MicroRNAs (miRNA), a class of natural RNA- interfering agents, have recently been identified as attractive targets for therapeutic intervention. The rationale for developing miRNA therapeutics is based on the premise that aberrantly expressed miRNAs play key roles in the development of human disease and that correcting these miRNA deficiencies by either antagonizing of restoring miRNA function may provide a therapeutic benefit. This new class of gene regulators is transcribed from the genome and binds primarily in the '3 untranslated region of mRNA; targets negatively regulating protein production by inducing mRNA cleavage, increasing mRNA decay or repressing mRNA translation.

[0004] Importantly, miRNAs play critical roles in the development and progression of several types of cancers. Indeed, several miRNAs are reported to act as tumor suppressors or oncogenes. Examples of miRNAs with oncogenic activity are miR-155 and miR-17-92; in contrast, miR-15a, miR-16 and miR-34 and let-7 families are tumor suppressor miRNAs. In all cases, gain or loss of a particular miRNA results in altered expression of an mRNA that is critical for cell maintenance, proliferation, apoptosis or differentiation. It has been shown that there is a relationship between a miRNA cluster, mir- 17-92, and the Myc oncogenic pathway. It has also been demonstrated that there is an interaction between let-7 miRNA and the RAS proto oncogene. In summary, although they are tiny, microRNAs can have large-scale effects because they regulate a variety of genes and have been linked to the development of cancer. The discovery of miRNAs has added an entirely new dimension to antitumor therapeutic approaches. The invention provides for the delivery of stable miRNAs/miRNA inhibitors into cells as a therapeutic regimen.

SUMMARY OF THE INVENTION

[0005] The present invention is based on methods for treating cancer by administering a microparticle containing microRNA to a patient. The present invention also provides methods for downregulating a cancer associated protein by contacting a tumor cell with a microparticle containing microRNA. The present invention also provides kits comprising microparticles for use in the methods of the invention.

[0006] The present invention provides a method of treating cancer comprising administering a Wharton' s Jelly cell derived microparticle to a patient in need thereof, thereby treating the cancer. In one aspect, the microparticle targets cancer cells. In an additional aspect, the microparticle comprises exogenous microRNA. In certain aspects, the microRNA is miR-34, miR-192, miR-145, miR-143, miR-16-l„ miR125b, miR-30, miR-128, miR-504, miR380, miR-33, miR-25, miR-449, miR-215, miR605, miR-29, miR-17-92, miR-21, let-7, miR-15/16, miR-200 or miR-34. In one aspect, the administration of the microparticle downregulates a cancer associated protein. In an additional aspect, the cancer associated protein is E2F 1, HBP 1, CDKN1A, NCOA3, ERa, PTEN, MECP2, HOXA5, VPS4B, MYCN, RAB 14, DPYSL2, TGFBR2, TSGl Ol, ARHGAP12, BACEl, PDCD4, PTEN, RECK, PPARa, TIMP3, FasL, TGFBR2, SERINB5, CDK2AP1 , TPM1, CDKN1B, KIT, PPP2R2A, p27kipl, CDKNIC, ERa, KIT, DDIT4, BNIP3L, ZEB2, TBKl, CREBZF, MYBLl, DKK2, NIRF, NF2, CASP3, TRIM71 , BACEl, DMTF l , C22orf5, BCL2, ARL2, CCNT2, TPPP3, VEGFA, RARS, FGF2, ZNF622, DNAJB4, PURA, SHOC2, LUZP 1, FNDC3B, ITGA2, ATG9A, CA12, TMEM43, YIF 1B, TMEM189, VTI1B, RTN4, TOMM34, NAA15, PNP, SRPR, IP04, NAPg, PFAH1B2, SLC 12A2, SEC24A, NOTCH2, PPP2R5C, KCNN4, UBE4A, KPN A3, RAB30, ACP2, SRPRB, EIF4E, ABCF2, TPM3, ARHGDIA, GALNT7, LYPLA2, CHORDC 1, TMEM109, LAMC1 , EGFR, GPAM, ADSS, PPIF, RFT1 , TNFSF9, IGF2R, TXN2, GFPT1 , SLC7A1, SQSTM1 , PANX1, UTP15, NPR3, SLC 16A3, PTGS2, HARS, LAMTOR3, HSPA1B, ZEB 1, CTNNB 1, BAP1, GEMIN2, PTPRD, WDR37, KLF 1 1, SEPT9, HOXB5, ERBB2IP. KLHL20, FOG2, RIN2, RASSF2, ELM02, TCF7L1 , VAC 14, SHC1 , SEPT7, FOG2, SIRT1, BCL2, YY1, MYC, CDK6, CCND 1, FOXP 1, HNF4a, CDKN2C, ACSL4, LEF 1 , ACSL 1, MTA2, AXL, LDHA, HDAC 1, CD44, BCL2, E2F3, SIRT1, BCL2, CCND1, NMYC, MDM2, IGF-1 , DHFR, MYC, CDK4, OCT4, SOX2, KRAS, ELK1 , KLF4, MCL1, CCNE1 , CDK6, HDAC 1, p85a, CDC42 or Cyclin Gl . In another aspect, the cancer is breast cancer, lung cancer, colorectal cancer, pancreatic cancer, head and neck cancer, brain cancer, melanoma, skin cancer, prostate cancer, thyroid cancer, kidney cancer or bladder cancer. In a further aspect, the method further comprises administering a chemotherapeutic agent or radiation.

[0007] In another embodiment, the present invention provides for a method of downregulating a cancer associated protein comprising identifying the cancer associated protein in a tumor sample; generating a Wharton' s Jelly cell derived microparticle comprising microRNA; and contacting the tumor with the microparticle, thereby downregulating the cancer associated protein. In one aspect, the cancer associated protein is E2F 1, HBP 1, CDKN1A, NCOA3, ERa, PTEN, MECP2, HOXA5, VPS4B, MYCN, RAB 14, DPYSL2, TGFBR2, TSGlOl , ARHGAP12, BACEl , PDCD4, PTEN, RECK, PPARa, TIMP3, FasL, TGFBR2, SERINB5, CDK2AP1, TPM1 , CDKN1B, KIT, PPP2R2A, p27kip l, CDKNIC, ERa, KIT, DDIT4, BNIP3L, ZEB2, TBKl, CREBZF, MYBLl, DKK2, NIRF, NF2, CASP3, TRIM71, BACEl, DMTF l, C22orf5, BCL2, ARL2, CCNT2, TPPP3, VEGFA, RARS, FGF2, ZNF622, DNAJB4, PURA, SHOC2, LUZP l, F DC3B, ITGA2, ATG9A, CA12, TMEM43, YIFIB, TMEM189, VTIIB, RTN4, TOMM34, NAA15, PNP, SRPR, IP04, NAPg, PFAH1B2, SLC12A2, SEC24A, NOTCH2, PPP2R5C, KCNN4, UBE4A, KPN A3, RAB30, ACP2, SRPRB, EIF4E, ABCF2, TPM3, ARHGDIA, GALNT7, LYPLA2, CHORDC1, TMEM109, LAMC1, EGFR, GPAM, ADSS, PPIF, RFTl, TNFSF9, IGF2R, TXN2, GFPTl, SLC7A1, SQSTMl, PANXl, UTP15, NPR3, SLC16A3, PTGS2, HARS, LAMTOR3, HSPA1B, ZEB1, CTNNBl, BAPl, GEMIN2, PTPRD, WDR37, KLFl l, SEPT9, HOXB5, ERBB2IP. KLHL20, FOG2, RIN2, RASSF2, ELM02, TCF7L1, VAC 14, SHC1, SEPT7, FOG2, SIRTl, BCL2, YY1, MYC, CDK6, CCNDl, FOXP1, HNF4a, CDKN2C, ACSL4, LEF1, ACSL 1, MTA2, AXL, LDHA, HDACl, CD44, BCL2, E2F3, SIRTl, BCL2, CCNDl, NMYC, MDM2, IGF-1, DHFR, MYC, CDK4, OCT4, SOX2, KRAS, ELK1, KLF4, MCL1, CCNEl, CDK6, HDACl, p85a, CDC42 or Cyclin Gl . In an additional aspect, the microparticle is transfected with exogenous microRNA. In a further aspect, the microRNA is miR-34, miR-192, miR-145, miR-143, miR- 16-1,, miR125b, miR-30, miR-128, miR-504, miR380, miR-33, miR-25, miR-449, miR-215, miR605, miR-29, miR-17-92, miR-21, let-7, miR-15/16, miR-200 or miR-34. In one aspect, the cancer is breast cancer, lung cancer, colorectal cancer, pancreatic cancer, head and neck cancer, brain cancer, melanoma, skin cancer, prostate cancer, thyroid cancer, kidney cancer or bladder cancer.

[0008] In an additional embodiment, the present invention provides a composition comprising a Wharton' s Jelly cell derived microparticle and exogenous microRNA. In an additional aspect, the exogenous microRNA downregulates a cancer associated protein. In another aspect, the microRNA is miR-34, miR-192, miR-145, miR-143, miR- 16-1,, miR125b, miR-30, miR-128, miR-504, miR380, miR-33, miR-25, miR-449, miR- 215, miR605, miR-29, miR-17-92, miR-21 , let-7, miR-15/16, miR-200 or miR-34.

[0009] In a further embodiment, the present invention provides a kit for the downregulation of a cancer associated protein comprising a Wharton's Jelly cell derived microparticle and instructions for use. In another aspect, the microparticle is transfected with exogenous microRNA. In an additional aspect, the microRNA is miR-34, miR-192, miR-145, miR-143, miR-16-l„ miR125b, miR-30, miR-128, miR-504, miR380, miR- 33, miR-25, miR-449, miR-215, miR605, miR-29, miR-17-92, miR-21 , let-7, miR- 15/16, miR-200 or miR-34. In one aspect, the cancer associated protein is E2F 1, HBP1, CDKN1A, NCOA3, ERa, PTEN, MECP2, HOXA5, VPS4B, MYCN, RAB 14, DPYSL2, TGFBR2, TSG101, ARHGAP 12, BACE1, PDCD4, PTEN, RECK, PPARa, TIMP3, FasL, TGFBR2, SERINB5, CDK2AP1, TPM1, CDKN1B, KIT, PPP2R2A, p27kip l, CDKN1C, ERa, KIT, DDIT4, BNIP3L, ZEB2, TBK1 , CREBZF, MYBL1 , DKK2, NIRF, NF2, CASP3, TRIM71 , BACE1, DMTF 1, C22orf5, BCL2, ARL2, CCNT2, TPPP3, VEGFA, RARS, FGF2, ZNF622, DNAJB4, PURA, SHOC2, LUZP1 , FNDC3B, ITGA2, ATG9A, CA12, TMEM43, YIF 1B, TMEM189, VTI1B, RTN4, TOMM34, NAA15, PNP, SRPR, IP04, NAPg, PFAH1B2, SLC 12A2, SEC24A, NOTCH2, PPP2R5C, KCNN4, UBE4A, KPNA3, RAB30, ACP2, SRPRB, EIF4E, ABCF2, TPM3, ARHGDIA, GALNT7, LYPLA2, CHORDC1, TMEM109, LAMC 1, EGFR, GPAM, ADSS, PPIF, RFT1, TNFSF9, IGF2R, TXN2, GFPT1, SLC7A1, SQSTM1, PANX1 , UTP15, NPR3, SLC 16A3, PTGS2, HARS, LAMTOR3, HSPA1B, ZEB 1 , CTNNB l, BAP1, GEMIN2, PTPRD, WDR37, KLF 1 1 , SEPT9, HOXB5, ERBB2IP. KLHL20, FOG2, RIN2, RASSF2, ELM02, TCF7L1, VAC 14, SHC 1, SEPT7, FOG2, SIRT1, BCL2, YY1, MYC, CDK6, CCND1, FOXP1, HNF4a, CDKN2C, ACSL4, LEF 1 , ACSL 1 , MTA2, AXL, LDHA, HDAC 1, CD44, BCL2, E2F3, SIRT1, BCL2, CCND1, NMYC, MDM2, IGF-1 , DHFR, MYC, CDK4, OCT4, SOX2, KRAS, ELK1 , KLF4, MCL1 , CCNE1 , CDK6, HD AC 1 , p85a, CDC42 or Cyclin Gl .

BRIEF DESCRIPTION OF THE FIGURES

[0010] Figures 1A-C show the activation and functions of the p53 tumor suppressor and their cellular effects. Figure 1A Key proteins participating in the activation and posttranscriptional control of p53 in response to cellular stress are shown. Figure IB Functions of p53 dependent on its role as a transcription factor are summarized here. Representative examples of p53 activated proteins and miRNAs are shown, as are a selection of targets for each miRNA. Figure 1C Transcription-independent functions of p53 relying on its participation in protein-protein interactions. Examples of miRNAs upregulated post-transcriptionally by p53 and a selection of their target genes are shown. Examples of apoptotic regulators bound by p53 are shown.

[0011] Figure 2 shows the regulation of p53. Left: miRNAs directly repressing p53 through binding to sites in the p53 3'UTR. Right: Examples of miRNAs positively regulating p53 through repression of a selection of other targets that antagonize p53 function. Block arrows indicate repression. Feedback loops where p53 is also capable of increasing the miRNA levels are indicated with arced arrows. [0012] Figures 3A-C show the processing of the umbilical cord to isolate Wharton' s Jelly cells. Figure 3A shows an umbilical cord. Figure 3B shows a partially processed umbilical cord. Figure 3C shows that veins and arteries are removed prior to further processing.

[0013] Figures 4A-C show the isolation of MSCs from WJCs. Figure 4A shows the enzymatic digestion of WJCs. Figures 4B-C show isolated MSCs.

[0014] Figures 5A-B show the formation of microparticles (MPs) from the MSCs. Figure 5A show the formation of MPs on the MSCs. Figure 5B shows the release of a MP from the MSC.

[0015] Figures 6A-B are magnified views of isolated MPs. Figure 6A shows 16,000X magnification and Figure 6B shows 30,000x magnification. The arrows point to MPs of various sizes.

[0016] Figures 7A-C show the selective targeting of MPs to cancer cells and the transfer of genetic material to the cancer cell. Figure 7A shows the MP uptake at the cancer cell. Figure 7B shows MPs on the surface of the cancer cell. Figure 7C shows miRNA uptake from the MP to the cancer cell.

[0017] Figures 8A-B show the biodistribution and homing kinetics of MPs in an orthotopic cancer model. Figure 8A shows flow cytometric analysis of the distribution of DiD labelled MPs in mice. Figure 8B shows clusters of WJC derived MPs.

[0018] Figures 9A-C show the reduction of tumor burden following administration of MPs. Figure 9A shows day 0 following administration. Figure 9B shows day 10 following administration. Figure 9C shows day 15 following administration.

DETAILED DESCRIPTION OF THE INVENTION

[0019] The present invention is based on methods for treating cancer by administering a microparticle containing microRNA to a patient. The present invention also provides methods for downregulating a cancer associated protein by contacting a tumor cell with a microparticle containing microRNA. The present invention also provides kits comprising microparticles for use in the methods of the invention.

[0020] Before the present compositions and methods are described, it is to be understood that this invention is not limited to particular compositions, methods, and experimental conditions described, as such compositions, methods, and conditions may vary. It is also to be understood that the terminology used herein is for purposes of describing particular embodiments only, and is not intended to be limiting, since the scope of the present invention will be limited only in the appended claims.

[0021] As used in this specification and the appended claims, the singular forms "a", "an", and "the" include plural references unless the context clearly dictates otherwise. Thus, for example, references to "the method" includes one or more methods, and/or steps of the type described herein which will become apparent to those persons skilled in the art upon reading this disclosure and so forth.

[0022] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the invention, the preferred methods and materials are now described.

[0023] Cancer is a malignant and invasive growth or tumor, especially one originating in epithelium, tending to recur after excision and to metastasize to other sites or any disease characterized by such growths. As used herein, the terms "cancer cell" or "tumor cell" are used interchangeably and refer to individual cells of a cancerous growth or tumor.

[0024] Exemplary cancers described by the national cancer institute include: Acute Lymphoblastic Leukemia, Adult; Acute Lymphoblastic Leukemia, Childhood; Acute Myeloid Leukemia, Adult; Adrenocortical Carcinoma; Adrenocortical Carcinoma, Childhood; AIDS-Related Lymphoma; AIDS-Related Malignancies; Anal Cancer; Astrocytoma, Childhood Cerebellar; Astrocytoma, Childhood Cerebral; Bile Duct Cancer, Extrahepatic; Bladder Cancer; Bladder Cancer, Childhood; Bone Cancer, Osteosarcoma/Malignant Fibrous Histiocytoma; Brain Stem Glioma, Childhood; Brain Tumor, Adult; Brain Tumor, Brain Stem Glioma, Childhood; Brain Tumor, Cerebellar Astrocytoma, Childhood; Brain Tumor, Cerebral Astrocytoma/Malignant Glioma, Childhood; Brain Tumor, Ependymoma, Childhood; Brain Tumor, Medulloblastoma, Childhood; Brain Tumor, Supratentorial Primitive Neuroectodermal Tumors, Childhood; Brain Tumor, Visual Pathway and Hypothalamic Glioma, Childhood; Brain Tumor, Childhood (Other); Breast Cancer; Breast Cancer and Pregnancy; Breast Cancer, Childhood; Breast Cancer, Male; Bronchial Adenomas/Carcinoids, Childhood: Carcinoid Tumor, Childhood; Carcinoid Tumor, Gastrointestinal; Carcinoma, Adrenocortical; Carcinoma, Islet Cell; Carcinoma of Unknown Primary; Central Nervous System Lymphoma, Primary; Cerebellar Astrocytoma, Childhood; Cerebral Astrocytoma/Malignant Glioma, Childhood; Cervical Cancer; Childhood Cancers; Chronic Lymphocytic Leukemia; Chronic Myelogenous Leukemia; Chronic Myeloproliferative Disorders; Clear Cell Sarcoma of Tendon Sheaths; Colon Cancer; Colorectal Cancer, Childhood; Cutaneous T-Cell Lymphoma; Endometrial Cancer; Ependymoma, Childhood; Epithelial Cancer, Ovarian; Esophageal Cancer; Esophageal Cancer, Childhood; Ewing's Family of Tumors; Extracranial Germ Cell Tumor, Childhood; Extragonadal Germ Cell Tumor; Extrahepatic Bile Duct Cancer; Eye Cancer, Intraocular Melanoma; Eye Cancer, Retinoblastoma; Gallbladder Cancer; Gastric (Stomach) Cancer; Gastric (Stomach) Cancer, Childhood; Gastrointestinal Carcinoid Tumor; Germ Cell Tumor, Extracranial, Childhood; Germ Cell Tumor, Extragonadal; Germ Cell Tumor, Ovarian; Gestational Trophoblastic Tumor; Glioma. Childhood Brain Stem; Glioma. Childhood Visual Pathway and Hypothalamic; Hairy Cell Leukemia; Head and Neck Cancer; Hepatocellular (Liver) Cancer, Adult (Primary); Hepatocellular (Liver) Cancer, Childhood (Primary); Hodgkin's Lymphoma, Adult; Hodgkin's Lymphoma, Childhood; Hodgkin's Lymphoma During Pregnancy; Hypopharyngeal Cancer; Hypothalamic and Visual Pathway Glioma, Childhood; Intraocular Melanoma; Islet Cell Carcinoma (Endocrine Pancreas); Kaposi's Sarcoma; Kidney Cancer; Laryngeal Cancer; Laryngeal Cancer, Childhood; Leukemia, Acute Lymphoblastic, Adult; Leukemia, Acute Lymphoblastic, Childhood; Leukemia, Acute Myeloid, Adult; Leukemia, Acute Myeloid, Childhood; Leukemia, Chronic Lymphocytic; Leukemia, Chronic Myelogenous; Leukemia, Hairy Cell; Lip and Oral Cavity Cancer; Liver Cancer, Adult (Primary); Liver Cancer, Childhood (Primary); Lung Cancer, Non-Small Cell; Lung Cancer, Small Cell; Lymphoblastic Leukemia, Adult Acute; Lymphoblastic Leukemia, Childhood Acute; Lymphocytic Leukemia, Chronic; Lymphoma, AIDS— Related; Lymphoma, Central Nervous System (Primary); Lymphoma, Cutaneous T-Cell; Lymphoma, Hodgkin's, Adult; Lymphoma, Hodgkin's; Childhood; Lymphoma, Hodgkin's During Pregnancy; Lymphoma, Non-Hodgkin's, Adult; Lymphoma, Non-Hodgkin's, Childhood; Lymphoma, Non-Hodgkin's During Pregnancy; Lymphoma, Primary Central Nervous System; Macroglobulinemia, Waldenstrom's; Male Breast Cancer; Malignant Mesothelioma, Adult; Malignant Mesothelioma, Childhood; Malignant Thymoma; Medulloblastoma, Childhood; Melanoma; Melanoma, Intraocular; Merkel Cell Carcinoma; Mesothelioma, Malignant; Metastatic Squamous Neck Cancer with Occult Primary; Multiple Endocrine Neoplasia Syndrome, Childhood; Multiple Myeloma/Plasma Cell Neoplasm; Mycosis Fungoides; Myelodysplastic Syndromes; Myelogenous Leukemia, Chronic; Myeloid Leukemia, Childhood Acute; Myeloma, Multiple; Myeloproliferative Disorders, Chronic; Nasal Cavity and Paranasal Sinus Cancer; Nasopharyngeal Cancer; Nasopharyngeal Cancer, Childhood; Neuroblastoma; Non-Hodgkin's Lymphoma, Adult; Non-Hodgkin's Lymphoma, Childhood; Non-Hodgkin's Lymphoma During Pregnancy; Non-Small Cell Lung Cancer; Oral Cancer, Childhood; Oral Cavity and Lip Cancer; Oropharyngeal Cancer; Osteosarcoma/Malignant Fibrous Histiocytoma of Bone; Ovarian Cancer, Childhood; Ovarian Epithelial Cancer; Ovarian Germ Cell Tumor; Ovarian Low Malignant Potential Tumor; Pancreatic Cancer; Pancreatic Cancer, Childhood', Pancreatic Cancer, Islet Cell; Paranasal Sinus and Nasal Cavity Cancer; Parathyroid Cancer; Penile Cancer; Pheochromocytoma; Pineal and Supratentorial Primitive Neuroectodermal Tumors, Childhood; Pituitary Tumor; Plasma Cell Neoplasm/Multiple Myeloma; Pleuropulmonary Blastoma; Pregnancy and Breast Cancer; Pregnancy and Hodgkin's Lymphoma; Pregnancy and Non-Hodgkin's Lymphoma; Primary Central Nervous System Lymphoma; Primary Liver Cancer, Adult; Primary Liver Cancer, Childhood; Prostate Cancer; Rectal Cancer; Renal Cell (Kidney) Cancer; Renal Cell Cancer, Childhood; Renal Pelvis and Ureter, Transitional Cell Cancer; Retinoblastoma; Rhabdomyosarcoma, Childhood; Salivary Gland Cancer; Salivary Gland'Cancer, Childhood; Sarcoma, Ewing's Family of Tumors; Sarcoma, Kaposi's; Sarcoma (Osteosarcoma)/Malignant Fibrous Histiocytoma of Bone; Sarcoma, Rhabdomyosarcoma, Childhood; Sarcoma, Soft Tissue, Adult; Sarcoma, Soft Tissue, Childhood; Sezary Syndrome; Skin Cancer; Skin Cancer, Childhood; Skin Cancer (Melanoma); Skin Carcinoma, Merkel Cell; Small Cell Lung Cancer; Small Intestine Cancer; Soft Tissue Sarcoma, Adult; Soft Tissue Sarcoma, Childhood; Squamous Neck Cancer with Occult Primary, Metastatic; Stomach (Gastric) Cancer; Stomach (Gastric) Cancer, Childhood; Supratentorial Primitive Neuroectodermal Tumors, Childhood; T- Cell Lymphoma, Cutaneous; Testicular Cancer; Thymoma, Childhood; Thymoma, Malignant; Thyroid Cancer; Thyroid Cancer, Childhood; Transitional Cell Cancer of the Renal Pelvis and Ureter; Trophoblastic Tumor, Gestational; Unknown Primary Site, Cancer of, Childhood; Unusual Cancers of Childhood; Ureter and Renal Pelvis, Transitional Cell Cancer; Urethral Cancer; Uterine Sarcoma; Vaginal Cancer; Visual Pathway and Hypothalamic Glioma, Childhood; Vulvar Cancer; Waldenstrom's Macro globulinemia; and Wilms' Tumor.

[0025] As used herein, the term "cancer associated protein" refers to any protein associated with the development or furtherance of cancer or any protein that is upregulated or downregulated in cancer. Examples of cancer related proteins include, but are not limited to, E2F 1, HBP l, CDKNIA, NCOA3, ERa, PTEN, MECP2, HOXA5, VPS4B, MYCN, RAB 14, DPYSL2, TGFBR2, TSG101, ARHGAP12, BACE1, PDCD4, PTEN, RECK, PPARa, TIMP3, FasL, TGFBR2, SERINB5, CDK2AP1, TPM1, CDKN1B, KIT, PPP2R2A, p27kip l, CDKN1 C, ERa, KIT, DDIT4, BNIP3L, ZEB2, TBK1, CREBZF, MYBL1 , DKK2, NIRF, NF2, CASP3, TRIM71, BACE1, DMTF 1, C22orf5, BCL2, ARL2, CCNT2, TPPP3, VEGFA, RARS, FGF2, ZNF622, DNAJB4, PURA, SHOC2, LUZP 1, FNDC3B, ITGA2, ATG9A, CA12, TMEM43, YIF 1B, TMEM189, VTI1B, RTN4, TOMM34, NAA15, PNP, SRPR, IP04, NAPg, PFAH1B2, SLC 12A2, SEC24A, NOTCH2, PPP2R5C, KCNN4, UBE4A, KPN A3 , RAB30, ACP2, SRPRB, EIF4E, ABCF2, TPM3, ARHGDIA, GALNT7, LYPLA2, CHORDC1 , TMEM109, LAMC 1, EGFR, GPAM, ADSS, PPIF, RFT1, TNFSF9, IGF2R, TXN2, GFPT1 , SLC7A1, SQSTM1, PANX1, UTP15, NPR3, SLC 16A3, PTGS2, HARS, LAMTOR3, HSPA1B, ZEB 1, CTNNB 1, BAP 1, GEMIN2, PTPRD, WDR37, KLF 1 1 , SEPT9, HOXB5, ERBB2IP. KLHL20, FOG2, RIN2, RASSF2, ELM02, TCF7L1 , VAC 14, SHC 1, SEPT7, FOG2, SIRT1 , BCL2, YY1, MYC, CDK6, CCND1, FOXP1, HNF4a, CDKN2C, ACSL4, LEF 1 , ACSL 1 , MTA2, AXL, LDHA, HDAC l, CD44, BCL2, E2F3, SIRT1, BCL2, CCND1, NMYC, MDM2, IGF-1, DHFR, MYC, CDK4, OCT4, SOX2, KRAS, ELKl , KLF4, MCLl, CCNEl, CDK6, HDAC l, p85a, CDC42 or Cyclin Gl .

[0026] As used herein, the terms "treatment", "treat" or "treating" refer to any method of preventing, treating, or ameliorating the damage caused by cancer. Typical treatment for cancer includes the administration of ch em other apeutic agents, radiation and surgery.

[0027] Exemplary ch em other apeutic agents described by the national cancer institute include: Abiraterone Acetate, Abitrexate (Methotrexate), Abraxane (Paclitaxel Albumin), ABVD, ABVE, ABVE-PC, AC, AC-T, Adcetris (Brentuximab Vedotin), ADE, Ado-Trastuzumab Emtansine, Adriamycin (Doxorubicin Hydrochloride), Afatinib Dimaleate, Afinitor (Everolimus), Akynzeo (Netupitant and Palonosetron Hydrochloride), Aldara (Imiquimod), Aldesleukin, Alecensa (Alectinib), Alectinib, Alemtuzumab, Alkeran for Injection (Melphalan Hydrochloride), Alkeran Tablets(Melphalan), Alimta (Pemetrexed Disodium), Aloxi (Palonosetron Hydrochloride), Ambochlorin (Chlorambucil), Amboclorin (Chlorambucil), Aminolevulinic Acid, Anastrozole, Aprepitant, Aredia (Pamidronate Disodium), Arimidex (Anastrozole), Aromasin (Exemestane), Arranon (Nelarabine), Arsenic Trioxide, Arzerra (Ofatumumab), Asparaginase Erwinia chrysanthemi, Avastin (Bevacizumab), Axitinib, Azacitidine, BEACOPP Becenum (Carmustine), Beleodaq (Belinostat), Belinostat, Bendamustine Hydrochloride, BEP, Bevacizumab, Bexarotene, Bexxar (Tositumomab and Iodine I 131 Tositumomab), Bicalutamide, BiCNU (Carmustine), Bleomycin, Blinatumomab, Blincyto (Blinatumomab), Bortezomib, Bosulif (Bosutinib), Bosutinib, Brentuximab Vedotin, Busulfan, Busulfex (Busulfan), Cabazitaxel, Cabozantinib-S-Malate, CAF, Campath (Alemtuzumab), Camptosar (Irinotecan Hydrochloride), Capecitabine, CAPOX, Carac (Fluorouracil), Carboplatin, CARBOPLATIN-TAXOL, Carfilzomib, Carmubris (Carmustine), Carmustine, Carmustine Implant, Casodex (Bicalutamide), CeeNU (Lomustine), CEM, Ceritinib, Cerubidine (Daunorubicin Hydrochloride), Cervarix (Recombinant HPV Bivalent Vaccine), Cetuximab, Chlorambucil, CHLORAMBUCIL-PREDNISONE, CHOP, Cisplatin, Clafen (Cyclophosphamide), Clofarabine, Clofarex (Clofarabine), Clolar (Clofarabine), CMF, Cobimetinib, Cometriq (Cabozantinib-S-Malate), COPDAC, COPP, COPP-ABV, Cosmegen (Dactinomycin), Cotellic (Cobimetinib), Crizotinib,CVP, Cyclophosphamide, Cyfos (Ifosfamide), Cyramza (Ramucirumab), Cytarabine, Cytarabine Liposome, Cytosar-U (Cytarabine), Cytoxan (Cyclophosphamide), Dabrafenib, Dacarbazine, Dacogen (Decitabine), Dactinomycin, Daratumumab, Darzalex (Daratumumab), Dasatinib, Daunorubicin Hydrochloride, Decitabine, Degarelix, Denileukin Diftitox, Denosumab, DepoCyt (Cytarabine Liposome), Dexamethasone, Dexrazoxane Hydrochloride, Dinutuximab, Docetaxel, Doxil (Doxorubicin Hydrochloride), Doxorubicin Hydrochloride, Dox-SL (Doxorubicin Hydrochloride), DTIC-Dome (Dacarbazine), Efudex (Fluorouracil), Elitek (Rasburicase), Ellence (Epirubicin Hydrochloride), Elotuzumab, Eloxatin (Oxaliplatin), Eltrombopag Olamine, Emend (Aprepitant), Empliciti (Elotuzumab), Enzalutamide, Epirubicin Hydrochloride, EPOCH, Erbitux (Cetuximab), Eribulin Mesylate, Erivedge (Vismodegib), Erlotinib Hydrochloride, Erwinaze (Asparaginase Erwinia chrysanthemi), Etopophos (Etoposide Phosphate), Etoposide, Etoposide Phosphate, Evacet (Doxorubicin Hydrochloride Liposome), Everolimus, Evista (Raloxifene Hydrochloride), Evomela (Melphalan Hydrochloride), Exemestane, 5-FU (Fluorouracil), Fareston (Toremifene), Farydak (Panobinostat), Faslodex (Fulvestrant), FEC, Femara (Letrozole), Filgrastim, Fludara (Fludarabine Phosphate), Fludarabine Phosphate, Fluoroplex (Fluorouracil), Fluorouracil Inj ection, Flutamide, Folex (Methotrexate), Folex PFS (Methotrexate), FOLFIRI, FOLFIRI-BEVACIZUMAB, FOLFIRI-CETUXIMAB, FOLFIRINOX, FOLFOX, Folotyn (Pralatrexate), FU-LV, Fulvestrant, Gardasil (Recombinant HPV Quadrivalent Vaccine), Gardasil 9 (Recombinant HPV Nonavalent Vaccine), Gazyva (Obinutuzumab), Gefitinib, Gemcitabine Hydrochloride, GEMCITABINE-CISPLATIN, GEMCITABINE- OXALIPLATIN, Gemtuzumab Ozogamicin, Gemzar (Gemcitabine Hydrochloride), Gilotrif (Afatinib Dimaleate), Gleevec (Imatinib Mesylate), Gliadel (Carmustine Implant), Gliadel wafer (Carmustine Implant), Glucarpidase, Goserelin Acetate, Halaven (Eribulin Mesylate), Herceptin (Trastuzumab), HPV Bivalent Vaccine, Hycamtin (Topotecan Hydrochloride), Hyper-CVAD, Ibrance (Palbociclib), Ibritumomab Tiuxetan, Ibrutinib, ICE, Iclusig (Ponatinib Hydrochloride), Idamycin (Idarubicin Hydrochloride), Idarubicin Hydrochloride, Idelalisib, Ifex (Ifosfamide), Ifosfamide, Ifosfamidum (Ifosfamide), IL-2 (Aldesleukin), Imatinib Mesylate, Imbruvica (Ibrutinib), Imiquimod, Imlygic (Talimogene Laherparepvec), Inlyta (Axitinib), Interferon Alfa-2b, Recombinant, Interleukin-2 (Aldesleukin), Intron A (Recombinant Interferon Alfa-2b), Iodine I 13 1 Tositumomab and Tositumomab, Ipilimumab, Iressa (Gefitinib), Irinotecan Hydrochloride, Istodax (Romidepsin), Ixabepilone, Ixazomib Citrate, Ixempra (Ixabepilone), Jakafi (Ruxolitinib Phosphate), Jevtana (Cabazitaxel), Kadcyla (Ado-Trastuzumab Emtansine), Keoxifene (Raloxifene Hydrochloride), Kepivance (Palifermin), Keytruda (Pembrolizumab), Kyprolis (Carfilzomib), Lanreotide Acetate, Lapatinib Ditosylate, Lenalidomide, Lenvatinib Mesylate, Lenvima (Lenvatinib Mesylate), Letrozole, Leucovorin Calcium, Leukeran (Chlorambucil), Leuprolide Acetate, Levulan (Aminolevulinic Acid), Linfolizin (Chlorambucil), LipoDox (Doxorubicin Hydrochloride Liposome), Lomustine, Lonsurf (Trifluridine and Tipiracil Hydrochloride), Lupron (Leuprolide Acetate), Lynparza (Olaparib), Marqibo (Vincristine Sulfate Liposome), Matulane (Procarbazine Hydrochloride), Mechlorethamine Hydrochloride, Megestrol Acetate, Mekinist (Trametinib), Melphalan, Melphalan Hydrochloride, Mercaptopurine, Mesna, Mesnex (Mesna), Methazolastone (Temozolomide), Methotrexate, Methotrexate LPF (Methotrexate), Mexate (Methotrexate), Mexate-AQ (Methotrexate), Mitomycin C, Mitoxantrone Hydrochloride, Mitozytrex (Mitomycin C), MOPP, Mozobil (Plerixafor), Mustargen (Mechlorethamine Hydrochloride), Mutamycin (Mitomycin C), Myleran (Busulfan), Mylosar (Azacitidine), Mylotarg (Gemtuzumab Ozogamicin), Nanoparticle Paclitaxel, Navelbine (Vinorelbine Tartrate), Necitumumab, Nelarabine, Neosar (Cyclophosphamide), Netupitant and Palonosetron Hydrochloride, Neupogen (Filgrastim), Nexavar (Sorafenib Tosylate), Nilotinib, Ninlaro (Ixazomib Citrate), Nivolumab, Nolvadex (Tamoxifen Citrate), Nplate (Romiplostim), Obinutuzumab, Odomzo (Sonidegib), OEPA, Ofatumumab, OFF, Olaparib, Omacetaxine Mepesuccinate, Oncaspar (Pegaspargase), Ondansetron Hydrochloride, Onivyde (Irinotecan Hydrochloride Liposome), Ontak (Denileukin Diftitox), Opdivo (Nivolumab), OPPA, Osimertinib, Oxaliplatin, Paclitaxel, Paclitaxel Albumin-stabilized Nanoparticle Formulation, PAD, Palbociclib, Palifermin, Palonosetron Hydrochloride, Palonosetron Hydrochloride and Netupitant, Pamidronate Disodium, Panitumumab, Panobinostat, Paraplat (Carboplatin), Paraplatin (Carboplatin), Pazopanib Hydrochloride, PCV, Pegaspargase, Peginterferon Alfa-2b, PEG-Intron (Peginterferon Alfa-2b), Pembrolizumab, Pemetrexed Disodium, Perjeta (Pertuzumab), Pertuzumab, Platinol (Cisplatin), Platinol-AQ (Cisplatin), Plerixafor, Pomalidomide, Pomalyst (Pomalidomide), Ponatinib Hydrochloride, Portrazza (Necitumumab), Pralatrexate, Prednisone, Procarbazine Hydrochloride, Proleukin (Aldesleukin), Prolia (Denosumab), Promacta (Eltrombopag Olamine), Provenge (Sipuleucel-T), Purinethol (Mercaptopurine), Purixan (Mercaptopurine), Radium 223 Dichloride, Raloxifene Hydrochloride, Ramucirumab, Rasburicase, R-CHOP, R-CVP, Recombinant Human Papillomavirus (HPV), Recombinant Interferon Alfa-2b, Regorafenib, R-EPOCH, Revlimid (Lenalidomide), Rheumatrex (Methotrexate), Rituxan (Rituximab), Rituximab, Rolapitant Hydrochloride, Romidepsin, Romiplostim, Rubidomycin (Daunorubicin Hydrochloride), Ruxolitinib Phosphate, Sclerosol Intrapleural Aerosol (Talc), Siltuximab, Sipuleucel-T, Somatuline Depot (Lanreotide Acetate), Sonidegib, Sorafenib Tosylate, Sprycel (Dasatinib), STANFORD V, Sterile Talc Powder (Talc), Steritalc (Talc), Stivarga (Regorafenib), Sunitinib Malate, Sutent (Sunitinib Malate), Sylatron (Peginterferon Alfa-2b), Sylvant (Siltuximab), Synovir (Thalidomide), Synribo (Omacetaxine Mepesuccinate), Tabloid (Thioguanine), TAC, Tafinlar (Dabrafenib), Tagrisso (Osimertinib), Talc, Talimogene Laherparepvec, Tamoxifen Citrate, Tarabine PFS (Cytarabine), Tarceva (Erlotinib Hydrochloride), Targretin (Bexarotene), Tasigna (Nilotinib), Taxol (Paclitaxel), Taxotere (Docetaxel), Temodar (Temozolomide), Temozolomide, Temsirolimus, Thalidomide, Thalomid (Thalidomide), Thioguanine, Thiotepa, Tolak (Fluorouracil—Topical), Topotecan Hydrochloride, Toremifene, Torisel (Temsirolimus), Tositumomab and Iodine I 13 1 Tositumomab, Totect (Dexrazoxane Hydrochloride), TPF, Trabectedin, Trametinib, Trastuzumab, Treanda (Bendamustine Hydrochloride)Trifluridine and Tipiracil Hydrochloride, Trisenox (Arsenic Trioxide), Tykerb (Lapatinib Ditosylate), Unituxin (Dinutuximab), Uridine Triacetate, VAC, Vandetanib, VAMP, Varubi (Rolapitant Hydrochloride), Vectibix (Panitumumab), VelP, Velban (Vinblastine Sulfate), Velcade (Bortezomib), Velsar (Vinblastine Sulfate), Vemurafenib, Viadur (Leuprolide Acetate), Vidaza (Azacitidine), Vinblastine Sulfate, Vincasar PFS (Vincristine Sulfate), Vincristine Sulfate, Vinorelbine Tartrate, VIP, Vismodegib, Vistogard (Uridine Triacetate), Voraxaze (Glucarpidase), Vorinostat, Votrient (Pazopanib Hydrochloride), Wellcovorin (Leucovorin Calcium), Xalkori (Crizotinib), Xeloda (Capecitabine), XELIRI, XELOX, Xgeva (Denosumab), Xofigo (Radium 223 Dichloride), Xtandi (Enzalutamide), Yervoy (Ipilimumab), Yondelis (Trabectedin), Zaltrap (Ziv-Aflibercept), Zarxio (Filgrastim), Zelboraf (Vemurafenib), Zevalin (Ibritumomab Tiuxetan), Zinecard (Dexrazoxane Hydrochloride), Ziv- Aflibercept, Zofran (Ondansetron Hydrochloride), Zoladex (Goserelin Acetate), Zoledronic Acid, Zolinza (Vorinostat), Zometa (Zoledronic Acid), Zydelig (Idelalisib), Zykadia (Ceritinib), Zytiga and (Abiraterone Acetate).

[0028] As used herein, the term "Pharmaceutically acceptable carrier" refers to a substance that is non-toxic, biologically tolerable, and otherwise biologically suitable for administration to a subj ect, such as an inert substance, added to a pharmacological composition or otherwise used as a vehicle, carrier, or diluent to facilitate administration of an agent and that is compatible therewith. Examples of excipients include calcium carbonate, calcium phosphate, various sugars and types of starch, cellulose derivatives, gelatin, vegetable oils, and polyethylene glycols.

[0029] Non-coding RNA (ncRNA) is an RNA molecule that is not translated into a protein. Less-frequently used synonyms are non-protein-coding RNA (npcRNA), non- messenger RNA (nmRNA), functional RNA (fRNA) or simply RNA. The DNA sequence from which a functional non-coding RNA is transcribed is often called an RNA gene. Non-coding RNA genes include highly abundant and functionally important RNAs such as transfer RNAs (tRNAs) and ribosomal RNAs (rRNAs), as well as RNAs such as snoRNAs, microRNAs, siRNAs, snRNAs, exRNAs, piRNAs and scaRNAs and the long ncRNAs that include examples such as Xist and HOTAIR. The number of ncRNAs encoded within the human genome is unknown; however, recent transcriptomic and bioinformatic studies suggest the existence of thousands of ncRNAs. Since many of the newly identified ncRNAs have not been validated for their function, it is possible that many are non-functional. It is also likely that many ncRNAs are non functional, and are the product of spurious transcription.

[0030] Non-coding RNA have roles in several biological functions RNA splicing, DNA replication, gene regulation, genome defense, chromosome structure and also have a role in several diseases and disorders such as cancer, Autism, Alzheimer's disease and hearing loss. Many ncRNAs show abnormal expression patterns in cancerous tissues. These include miRNAs, long mRNA-like ncRNAs, GAS 5, SNORD50, telomerase RNA and Y RNAs. The miRNAs are involved in the large scale regulation of many protein coding genes, the Y RNAs are important for the initiation of DNA replication, telomerase RNA that serves as a primer for telomerase, an RNP that extends telomeric regions at chromosome ends . The direct function of the long mRNA-like ncRNAs is less clear.

[0031] MicroRNAs (miRNAs) are a class of non-coding RNA gene whose products are ~ 22 nt sequences that play important roles in the regulation of translation and degradation of mRNAs through base pairing to partially complementary sites in the untranslated regions (UTRs) of the message. Since the discovery of the founding members of the class, let-7 and lin-4 miRNAs in Caenorhabditis elegans, more than 300 miRNAs have been found in animals and plants. In animals, the expression of miRNAs has been shown to involve at least two processing steps. miRNAs are transcribed as long primary transcipts (pri -miRNAs), which may contain more than one miRNA. The primary transcript is processed in the nucleus to give one or more hairpin precursor sequences (pre-miRNAs). This processing step defines one end of the mature miRNA sequence, which is contained in one arm of the hairpin precursor. The hairpin precursor is exported to the cytoplasm where the mature miRNA is excised by the RNase Ill-like enzyme Dicer, suggesting a relationship with RNA interference (RNAi). [0032] miRNA expression seems to be altered in many human diseases, including cancer (Table 1). Tissue-specific/tissue-enriched miRNAs are often downregulated and play a role in cancer. For example, brain-specific neuromiR-124 is downregulated in glioblastomas and myomiR-1/206 are downregulated in RMS. Lung-specific pneumomiR-29 suppresses tumorigenicity in non-small cell lung cancer cells. Let-7, which is normally expressed at higher levels in normal lung, is downregulated in lung cancer and associated with poor survival. Moreover, miR-143 and miR-145 have been shown to be downregulated in breast, cervical, and colorectal.

TABLE 1

(Mishra and Merino, J. Clin. Invest. (2009) 1 19:21 19)

[0033] Inhibiting miRNA biogenesis tends to enhance tumorigenesis. Downregulation may be achieved through mutation or by epigenetic silencing of the miRNA, resulting in loss of tissue-specific miRNA synthesis and overexpression of pro- proliferation genes (i.e., oncogenes); these miRNAs normally function as tumor suppressors. Of course, miRNAs can also act as oncogenes. It was demonstrated that expression of specific miRNAs regulating skeletal muscle development, miR-l/miR-206 (also known as myomiRs), is reduced in rhabdomyosarcoma (RMS). RMS tumors, the most common soft tissue sarcomas in pediatric patients and young adults, are thought to arise from the skeletal muscle lineage, coexpressing markers of proliferation and myogenic differentiation. Reexpression of these myomiRs to physiological levels suppressed many aspects of the transformed phenotype and induced myogenic differentiation, raising the possibility that miRNA reexpression may represent effective differentiation therapy for RMS and perhaps other cancer types.

[0034] Reexpressing lost miRNA in a cell can deliver a dramatic effect, because miRNAs regulate a vast number of genes and pathways. Among the many genes that miRNAs can regulate are oncogenes and tumor suppressors, targets of drugs currently used in the clinic. Although a few miRNAs are overexpressed in cancer and seem to function as oncogenes themselves, a greater number of miRNAs have been shown to be downregulated in cancer and have the potential to act as tumor suppressors (i.e., Let-7, miR-15/miR-16, miR-l/miR-206, miR-29, miR-124, miR-143/miR-145; see Table 1). miRNA reexpression and downregulation have both been shown to have antitumor effects. Silencing an oncogenic miRNA could allow reexpression of tumor suppressor genes, while reexpressing a tumor suppressor miRNA could downregulate multiple oncogenes. Reexpression, to physiological levels, of tissue-specific miRNAs that are lost in cancer can induce the dedifferentiation of cancer cells.

[0035] Examples of miRNAs that down regulate proteins in cancer are well known in the art. Jansson and Lund (Jansson and Lund (2012) Mol Oncology 6:590) reviewed the role of miRNA in cancer. As shown in Figures 1 and 2, the p53 pathway provides many targets for miRNA to exert anti-proliferative effects. Additionally Hayes et al. (Hayes et al. (2014) Trends in Mol Med 20:460) also review miRNAs and their targets for the treatment of cancer. Several miRNAs and the proteins that are targeted are listed in Table 2.

TABLE 2

(Hayes et al., Trends in Mol. Med. (2014) 20: 8)

[0036] Like siRNAs, miRNAs are easy to synthesize and can potentially target any gene, including otherwise non-druggable targets. However, miRNA therapy has many advantages over the originally envisioned RNA interference-based therapeutics (siRNA therapy). The major advantage of miRNA therapy is that miRNA reexpression can influence the expression of hundreds of genes involved in many cellular pathways. While siRNA therapy is more gene-specific, miRNA therapy can target an array of different gene products, more closely resembling the action of the so-called "dirty drugs" used in the clinic today; in fact, both the sense and antisense strands of miRNAs might target different mRNAs. Moreover, dirty drugs typically target only a handful of gene products, whereas miRNAs can target hundreds of genes, casting miRNAs as "super" dirty drugs. miRNAs are evolutionarily conserved, and targeting the upregulation or downregulation of a tissue-specific tumor suppressor miRNA or oncogenic miRNA, respectively, to its "physiological level" may incite fewer of the nonspecific, off-target effects often associated with artificial siRNAs or currently available dirty drugs. miRNA therapy shares many of the disadvantages of siRNA- therapy, including delivery limitations, instability, and off target effects. A major obstacle to effective miRNA-based therapy is the requirement for successful delivery. Unlike many other drugs, miRNAs do not freely diffuse into cells; therefore, miRNAs may require special delivery approaches to achieve the desired effect. Moreover, small RNAs tend to be unstable and might be degraded upon entering a cell; new methods may be required to stabilize these small sequences. Another factor is that double- stranded RNA and unmethylated CpG sequences are potentially immunogenic; their presence might increase IFN production and induce an immune response in patients. Moreover, in the case of miRNA reexpression therapy of cancer, preventing miRNA expression from exceeding physiological levels also represents a therapeutic challenge.

[0037] To overcome these obstacles, microparticles can be used for in vivo delivery of miRNAs and tumor targeting. Microparticles (MPs) were first described as 'platelet dust' if was discovered that of eukaryotic cells have the ability to shed components off their plasma membrane into the extracellular space. MPs usually refer to intact vesicles formed from the plasma membrane, have heterogeneous density and size (0.1-1.0μιη) and can be easily separated from apoptotic bodies, exosomes and matrix vesicles by differential centrifugation. MPs originate from many cell types, including endothelial cells, platelets, monocytes, erythrocytes, smooth muscle cells and mesenchymal stem cells. Thus, there is a wide range of different types of MPs in the blood with circulating MPs in plasma predominantly derived from platelets. During cell activation by agonists or physical or chemical stress, including apoptosis and subsequent increase of intracellular calcium concentration, modifications of the plasma membrane, such as phosphatidylserine externalization, and an increase in bleb formation take place.

[0038] Numerous studies have demonstrated that MPs and more specifically platelet MPs are present in circulating blood contributing to vascular repair, remodeling, and atherosclerotic lesion formation. The intercellular transport of proteins by extracellular secretory membrane bodies has important implications: First, if surface proteins can be transferred, marker positivity could, at least in part, reflect the exposure to tissue- specific set of MPs rather than cellular progeny. Second, the release of vesicles by injured tissue may be a means of disposal of membrane microdomains that endow mononuclear cells with properties required for tissue repair. Because the formation of MPs is accompanied by selective enrichment of specific subsets of the proteome, the characterization of their protein content is pivotal to the understanding of their function. Besides proteins, MPs also contain non-coding regulatory RNA, known as microRNA (miRNA), which act as translational repressors. It has been estimated that the human genome encodes up to 1000 miRNAs, predicted to regulate a third of all genes.

[0039] The generation, composition and characterization of microparticles (MP) derived from mesenchymal cells of umbilical cord origin (Wharton's Jelly) is described below in the Examples. Regarding the composition of microparticles, the membranes consist mainly of lipids such as phosphatidylserine and several proteins. Specific MPs have been designed to retain their chemokine profile allowing them to home into tumor cells in vitro and in vivo and have also been designed to contain specific upregulated microRNA sequences with therapeutic potential directed against human and animal ailments.

[0040] Mesenchymal stem cells (MSCs) have been extensively studied and are appealing as antitumor therapy cell vehicles given their ease of expansion and transduction. The rationale for using MSCs for delivering therapeutic agents to tumors is based on the concept that MSCs have the ability to home from the bone marrow to sites of injured tissues. As the microenvironment of solid tumors is relative similar to that of injured sites, exogenous given MSCs may migrate and engraft with ease to tumor sites.

[0041] MSCs are non-hematopoietic stem cells that have an inherent ability both to self renew and to differentiate into multiple lineages including osteoclasts, chondrocytes and adipocytes. The cells are readily isolated from the stromal compartment of bone marrow, along with a number of other sources including adipose tissue, skeletal muscle, fetal blood, umbilical cord blood and even liposuction material. However, fetal MSCs appear to have greater expansion capacity in vitro and faster doubling time than adult MSCs, which may be due to their longer telomeres. Specifically fetal MSCs have been isolated from umbilical cord blood, umbilical vein subendothelium and the Wharton's j elly. Wharton's j elly cells (WJCs) have been isolated from three relatively indistinct regions: the perivascular zone, the intervascular zone and the subamnion. It is unknown whether MSCs isolated from the different compartments of the umbilical cord have different populations. However, WJCs share several common properties with umbilical cord blood MSCs and also display adult MSC surface markers suggesting that they are of the MSC family. The migration or homing ability of MSCs is thought to be due to the expression of chemokine or other surface receptors e.g. CXCR4, the receptor for stem cell-derived factor 1 (SDF-1). Tumors secrete factors that recruit cells from surrounding tissue as well as from the bone marrow to provide support and nutrition. Recent evidence suggests that many of the paracrine effects attributed to MSCs are actually mediated by the release of microparticles, which contain not only potentially beneficial proteins, but also pre-miRNAs the function of which still remains to be determined.

[0042] WJCs can be isolated from close to 100% of the samples, even from umbilical cords that are delayed in their processing up to 48 hours. Furthermore, this source of stem cells allows the rapid initial isolation of large numbers of cells, avoiding the necessity of extensive multiplication and potential epigenetic damage and maybe better tolerated following transplantation with less incidence of graft versus host disease. WJCs are CD45, CD34,CD14, CD33, CD56, CD3 1 and HLA class II negative; CD73, CD90, CD 105 and HLA class I positive, plastic adherent and multipotent. Additionally, WJCs express GD2 synthase, a marker that has been proposed to uniquely identify MSCs in a bone marrow aspirate. Most importantly, WJCs are karyotypically stable over many passages and so not lose anchorage dependence, contact inhibition or serum dependence as cancer cells. Moreover, when large numbers of WJCs were transplanted into SCID mice there was no evidence of tumor formation..

[0043] WJCs enriched in specific miRNAs could be activated in order to release miRNA-rich MPs. In turn, these WJC-derived MPs could target and fuse with tumor cells, in order to deliver miRNAs and down regulate specific targeted genes. Preliminary data has suggested that when PMPs are in close proximity with other cell types e.g. monocytes could transfer or induce miRNA changes in the receptor cell.

[0044] The Examples below describe the extraction of WJCs, characterization and MP production: MPs can be done through serum deprivation, apoptosis or activation of WJCs. The expression levels of specific miRNAs are then identified in the WJC-derived MPs. If low levels of the miRNA of interest are present then a transfection step of overexpression of miRNAs in WJCs is performed. Also described below in the Examples are in vitro experiments demonstrating the ability of WJC-derived MPs to fuse and transfer the miRNAs to cancer cells/tumors. Further, the Examples provide evidence of the downregulation of specific targets. The Examples additionally demonstrate the in vivo delivery of the WJCs-derived MPs.

[0045] The present invention provides a method of treating cancer comprising administering a Wharton' s Jelly cell derived microparticle to a patient in need thereof, thereby treating the cancer. In one aspect, the microparticle targets cancer cells. In an additional aspect, the microparticle comprises exogenous microRNA. In certain aspects, the microRNA is miR-34, miR-192, miR-145, miR-143, miR-16-1 , miR125b, miR-30, miR-128, miR-504, miR380, miR-33, miR-25, miR-449, miR-215, miR605, miR-29, miR-17-92, miR-21, let-7, miR-15/16, miR-200 or miR-34. In one aspect, the administration of the microparticle downregulates a cancer associated protein. In an additional aspect, the cancer associated protein is E2F 1, HBP 1, CDKN1A, NCOA3, ERa, PTEN, MECP2, HOXA5, VPS4B, MYCN, RAB 14, DPYSL2, TGFBR2, TSG101, ARHGAP12, BACE1, PDCD4, PTEN, RECK, PPARa, TIMP3, FasL, TGFBR2, SERINB5, CDK2AP1 , TPM1, CDKN1B, KIT, PPP2R2A, p27kipl, CDKN1C, ERa, KIT, DDIT4, BNIP3L, ZEB2, TBKl, CREBZF, MYBLl, DKK2, NIRF, NF2, CASP3, TRIM71 , BACE1, DMTF 1 , C22orf5, BCL2, ARL2, CCNT2, TPPP3, VEGFA, RARS, FGF2, ZNF622, DNAJB4, PURA, SHOC2, LUZP 1, FNDC3B, ITGA2, ATG9A, CA12, TMEM43, YIF 1B, TMEM189, VTI1B, RTN4, TOMM34, NAA15, PNP, SRPR, IP04, NAPg, PFAH1B2, SLC 12A2, SEC24A, NOTCH2, PPP2R5C, KCNN4, UBE4A, KPN A3, RAB30, ACP2, SRPRB, EIF4E, ABCF2, TPM3, ARHGDIA, GALNT7, LYPLA2, CHORDC 1, TMEM109, LAMC1 , EGFR, GPAM, ADSS, PPIF, RFT1 , TNFSF9, IGF2R, TXN2, GFPT1 , SLC7A1, SQSTM1 , PANX1, UTP15, NPR3, SLC 16A3, PTGS2, HARS, LAMTOR3, HSPA1B, ZEB 1, CTNNB 1, BAP1, GEMIN2, PTPRD, WDR37, KLF 1 1, SEPT9, HOXB5, ERBB2IP. KLHL20, FOG2, RIN2, RASSF2, ELM02, TCF7L1 , VAC 14, SHC1 , SEPT7, FOG2, SIRT1, BCL2, YY1, MYC, CDK6, CCND 1, FOXP 1, HNF4a, CDKN2C, ACSL4, LEF 1 , ACSL 1, MTA2, AXL, LDHA, HDAC 1, CD44, BCL2, E2F3, SIRT1, BCL2, CCND1, NMYC, MDM2, IGF-1 , DHFR, MYC, CDK4, OCT4, SOX2, KRAS, ELK1 , KLF4, MCL1, CCNE1 , CDK6, HDAC 1, p85a, CDC42, or Cyclin Gl . In another aspect, the cancer is breast cancer, lung cancer, colorectal cancer, pancreatic cancer, head and neck cancer, brain cancer, melanoma, skin cancer, prostate cancer, thyroid cancer, kidney cancer or bladder cancer. In a further aspect, the method further comprises administering a chemotherapeutic agent or radiation.

[0046] In another embodiment, the present invention provides for a method of downregulating a cancer associated protein comprising identifying the cancer associated protein in a tumor sample; generating a Wharton' s Jelly cell derived microparticle comprising microRNA; and contacting the tumor with the microparticle, thereby downregulating the cancer associated protein. In one aspect, the cancer associated protein is E2F 1, HBP 1, CDKN1A, NCOA3, ERa, PTEN, MECP2, HOXA5, VPS4B, MYCN, RAB 14, DPYSL2, TGFBR2, TSGlOl , ARHGAP12, BACEl , PDCD4, PTEN, RECK, PPARa, TIMP3, FasL, TGFBR2, SERINB5, CDK2AP1, TPM1 , CDKN1B, KIT, PPP2R2A, p27kip l, CDKN1C, ERa, KIT, DDIT4, BNIP3L, ZEB2, TBK1, CREBZF, MYBL1, DKK2, NIRF, NF2, CASP3, TRIM71, BACEl, DMTF 1, C22orf5, BCL2, ARL2, CCNT2, TPPP3, VEGFA, RARS, FGF2, ZNF622, DNAJB4, PURA, SHOC2, LUZP 1, FNDC3B, ITGA2, ATG9A, CA12, TMEM43, YIF 1B, TMEM189, VTI1B, RTN4, TOMM34, NAA15, PNP, SRPR, IP04, NAPg, PFAH1B2, SLC 12A2, SEC24A, NOTCH2, PPP2R5C, KCNN4, UBE4A, KPNA3, RAB30, ACP2, SRPRB, EIF4E, ABCF2, TPM3, ARHGDIA, GALNT7, LYPLA2, CHORDC 1, TMEM109, LAMC 1 , EGFR, GPAM, ADSS, PPIF, RFTl, TNFSF9, IGF2R, TXN2, GFPTl , SLC7A1, SQSTM1, PANX1 , UTP15, NPR3, SLC 16A3, PTGS2, HARS, LAMTOR3, HSPA1B, ZEB 1, CTNNB 1 , BAP1, GEMIN2, PTPRD, WDR37, KLF 1 1 , SEPT9, HOXB5, ERBB2IP. KLHL20, FOG2, RIN2, RASSF2, ELM02, TCF7L1, VAC 14, SHC 1, SEPT7, FOG2, SIRT1, BCL2, YY1, MYC, CDK6, CCND1 , FOXP1, HNF4a, CDKN2C, ACSL4, LEF 1 , ACSL 1, MTA2, AXL, LDHA, HDAC 1, CD44, BCL2, E2F3, SIRT1 , BCL2, CCND1 , NMYC, MDM2, IGF-1, DHFR, MYC, CDK4, OCT4, SOX2, KRAS, ELK1 , KLF4, MCL1 , CCNE1 , CDK6, HD AC 1 , p85a, CDC42, or Cyclin Gl . In an additional aspect, the microparticle is transfected with exogenous microRNA. In a further aspect, the microRNA is miR-34, miR-192, miR-145, miR-143, miR-16-l„ miR125b, miR-30, miR-128, miR-504, miR380, miR-33, miR-25, miR-449, miR-215, miR605, miR-29, miR-17-92, miR-21 , let-7, miR-15/16, miR-200 or miR-34. In one aspect, the cancer is breast cancer, lung cancer, colorectal cancer, pancreatic cancer, head and neck cancer, brain cancer, melanoma, skin cancer, prostate cancer, thyroid cancer, kidney cancer or bladder cancer. [0047] In an additional embodiment, the present invention provides a composition comprising a Wharton' s Jelly cell derived microparticle and exogenous microRNA. In an additional aspect, the exogenous microRNA downregulates a cancer associated protein. In another aspect, the microRNA is miR-34, miR-192, miR-145, miR-143, miR- 16-1,, miR125b, miR-30, miR-128, miR-504, miR380, miR-33, miR-25, miR-449, miR- 215, miR605, miR-29, miR-17-92, miR-21 , let-7, miR-15/16, miR-200 or miR-34.

[0048] In a further embodiment, the present invention provides a kit for the downregulation of a cancer associated protein comprising a Wharton's Jelly cell derived microparticle and instructions for use. In another aspect, the microparticle is transfected with exogenous microRNA. In an additional aspect, the microRNA miR-34, miR-192, miR-145, miR-143, miR-16-1 , miR125b, miR-30, miR-128, miR-504, miR380, miR-33, miR-25, miR-449, miR-215, miR605, miR-29, miR-17-92, miR-21, let-7, miR-15/16, miR-200 or miR-34. In one aspect, the cancer associated protein is E2F 1, HBP1, CDKN1A, NCOA3, ERa, PTEN, MECP2, HOXA5, VPS4B, MYCN, RAB 14, DPYSL2, TGFBR2, TSG101, ARHGAP 12, BACEl, PDCD4, PTEN, RECK, PPARa, TIMP3, FasL, TGFBR2, SERINB5, CDK2AP1, TPM1, CDKN1B, KIT, PPP2R2A, p27kip l, CDKN1C, ERa, KIT, DDIT4, BNIP3L, ZEB2, TBK1 , CREBZF, MYBL1 , DKK2, NIRF, NF2, CASP3, TRIM71 , BACEl, DMTF l, C22orf5, BCL2, ARL2, CCNT2, TPPP3, VEGFA, RARS, FGF2, ZNF622, DNAJB4, PURA, SHOC2, LUZP1 , FNDC3B, ITGA2, ATG9A, CA12, TMEM43, YIF 1B, TMEM189, VTI1B, RTN4, TOMM34, NAA15, PNP, SRPR, IP04, NAPg, PFAH1B2, SLC 12A2, SEC24A, NOTCH2, PPP2R5C, KCNN4, UBE4A, KPNA3, RAB30, ACP2, SRPRB, EIF4E, ABCF2, TPM3, ARHGDIA, GALNT7, LYPLA2, CHORDC1, TMEM109, LAMC 1, EGFR, GPAM, ADSS, PPIF, RFT1, TNFSF9, IGF2R, TXN2, GFPT1, SLC7A1, SQSTM1, PANX1 , UTP15, NPR3, SLC 16A3, PTGS2, HARS, LAMTOR3, HSPAIB, ZEB l , CTNNB l, BAP1, GEMIN2, PTPRD, WDR37, KLF 1 1 , SEPT9, HOXB5, ERBB2IP. KLHL20, FOG2, RIN2, RASSF2, ELM02, TCF7L1, VAC 14, SHC 1, SEPT7, FOG2, SIRT1, BCL2, YYl, MYC, CDK6, CCNDl, FOXPl, HNF4a, CDKN2C, ACSL4, LEF l , ACSL 1 , MTA2, AXL, LDHA, HDAC 1, CD44, BCL2, E2F3, SIRT1, BCL2, CCNDl, NMYC, MDM2, IGF-1 , DHFR, MYC, CDK4, OCT4, SOX2, KRAS, ELKl , KLF4, MCLl , CCNE1 , CDK6, HD AC 1 , p85a, CDC42, or Cyclin Gl .

[0049] The following examples are intended to illustrate but not limit the invention.

EXAMPLES EXAMPLE 1

[0050] MSCs were isolated from the Wharton' s j elly of human umbilical cords. The MSC cultures were subj ected to serum deprivation, leading to the formation of MPs (secreted membrane vehicles <1 μιη) which were harvested and characterized (Figures 3A-C). The veins and arteries are removed from the umbilical cord before enzymatic digestion and MSC isolation. Specifically, WJCs were subjected to a mixed enzymatic digestion using Collagenase, Hyaluronidase and Trypsin) (Figures 4A-C). The MSC cultures were subj ected to serum deprivation for 2 days leading to the generation of MPs which were secreted as intact membrane vesicles (<1 μπι) (Figures 5A-B). The MSC derived MPs were harvested and characterized by SEM, PCR, FACS, Fluorescence Microscopy & miRNA profiling. The generated MPs are of various sizes from approximately 0.1-1 μπι in diameter (Figure 6).

[0051] In vitro tests were performed and demonstrated that the MPs incorporate into cancer cells, transfer proteomic and genetic material into the cancer cells and reduced tumor cell proliferation. Different cell lines (breast, colon & ovarian adenocarcinoma) were exposed to MPs and the response to treatment was evaluated by cell morphology, proliferation, migration, gene expression and apoptosis assays. It was shown that MP preferentially migrate to the tumor cells. Further, MPs facilitate incorporation of miRNAs into the targeted tumor cells by fusing directly with the cell membrane (Figures 7A-C). MPs can carry multiple, pre-selected therapeutic miRNAs against cell targets for most cell types.

[0052] In vivo tests demonstrate the therapeutic potential of MPs. MP were administered to orthotopic tumor mouse models and the animals were analyzed by in vivo flow cytometry and whole body fluorescence-bioluminescence to dynamically investigate the biodistribution and homing kinetics of the MPs. Figure 8 shows flow cytometry analysis of DiD labeled MPs in the circulation measured by taking sequential 60 second data traces and plotted as a function of time after injection. Figure 9 shows the assessment of tumor burden via in vivo imaging demonstrated a reduction in tumor growth over time in mice treated with MP/miRNA complexes compared to untreated mice. The figure shows tumor response in treated mice at day 0, 10 and 15 post injections (representative images of the n number of mice tested).

[0053] In vitro experiments confirmed that MSC-derived MPs can be internalized by cancer cells and induce a biological effect as evidenced by damage/shrinkage of the recipient cell, induction of apoptosis, inhibition of cell proliferation and tumor growth attenuation in a dose-dependent manner. In vivo studies monitored and quantified fluorescently labelled MPs in circulation and detected the biodistribution and incorporation in cells and organs in healthy and tumor-bearing mice. MSC-MPs containing miRNAs possess tumor inhibitory properties, transfer miRNAs and affect the action of cancer genes.

[0054] Although the invention has been described with reference to the above example, it will be understood that modifications and variations are encompassed within the spirit and scope of the invention. Accordingly, the invention is limited only by the following claims.

Claims

What is claimed is:

1. A method of treating cancer comprising administering a Wharton's Jelly cell derived microparticle to a patient in need thereof, thereby treating the cancer.

2. The method of claim 1, wherein the microparticle targets cancer cells.

3. The method of claim 1, wherein the microparticle comprises exogenous microRNA.

4. The method of claim 3, wherein the microRNA is selected from the group consisting of miR-34, miR-192, miR-145, miR-143, miR-16-l„ miR125b, miR-30, miR-128, miR-504, miR380, miR-33, miR-25, miR-449, miR-215, miR605, miR-29, miR-17-92, miR- 21, let-7, miR-15/16, miR-200 and miR-34.

5. The method of claim 1, wherein the administration of the microparticle downregulates a cancer associate protein.

6. The method of claim 5, wherein the cancer associated protein is selected from the group consisting of E2F1, HBP1, CDKN1A, NCOA3, ERa, PTEN, MECP2, HOXA5, VPS4B, MYCN, RAB 14, DPYSL2, TGFBR2, TSG101, ARHGAP12, BACE1, PDCD4, PTEN, RECK, PPARa, TFMP3, FasL, TGFBR2, SERINB5, CDK2AP1, TPMl, CDKNIB, KIT, PPP2R2A, p27kipl, CDKN1C, ERa, KIT, DDIT4, BNIP3L, ZEB2, TBK1, CREBZF, MYBL1, DKK2, NIRF, NF2, CASP3, TRJM71, BACE1, DMTF1, C22orf5, BCL2, ARL2, CCNT2, TPPP3, VEGFA, RARS, FGF2, ZNF622, DNAJB4, PURA, SHOC2, LUZP1, FNDC3B, ITGA2, ATG9A, CA12, TMEM43, YIF1B, TMEM189, VTI1B, RTN4, TOMM34, NAA15, PNP, SRPR, IP04, NAPg, PFAH1B2, SLC12A2, SEC24A, NOTCH2, PPP2R5C, KCNN4, UBE4A, KPN A3, RAB30, ACP2, SRPRB, EIF4E, ABCF2, TPM3, ARHGDIA, GALNT7, LYPLA2, CHORDC1, TMEM109, LAMC1, EGFR, GPAM, ADSS, PPIF, RFTl, TNFSF9, IGF2R, TXN2, GFPTl, SLC7A1, SQSTMl, PANXl, UTP15, NPR3, SLC16A3, PTGS2, HARS, LAMTOR3, HSPA1B, ZEB1, CTNNB1, BAPl, GEMIN2, PTPRD, WDR37, KLFl l, SEPT9, HOXB5, ERBB2IP. KLHL20, FOG2, RIN2, RASSF2, ELM02, TCF7L1, VAC 14, SHC1, SEPT7, FOG2, SIRTl, BCL2, YY1, MYC, CDK6, CCNDl, FOXP1, HNF4a, CDKN2C, ACSL4, LEF1, ACSL 1, MTA2, AXL, LDHA, HDACl, CD44, BCL2, E2F3, SIRTl, BCL2, CCNDl, NMYC, MDM2, IGF-1, DHFR, MYC, CDK4, OCT4, SOX2, KRAS, ELK1, KLF4, MCL1, CCNE1, CDK6, HDACl, p85a, CDC42, and Cyclin Gl .

7. The method of claim 1, wherein the cancer is selected from the group consisting of: breast cancer, lung cancer, colorectal cancer, pancreatic cancer, head and neck cancer, brain cancer, melanoma, skin cancer, prostate cancer, thyroid cancer, kidney cancer and bladder cancer.

8. The method of claim 1 further comprising administering a chemotherapeutic agent or radiation.

9. A method of downregulating a cancer associated protein comprising:

a) identifying the cancer associated protein in a tumor sample; b) generating a Wharton's Jelly cell derived microparticle comprising microRNA; and

c) contacting the tumor with the microparticle,

thereby downregulating the cancer associated protein.

10. The method of claim 9, wherein the cancer associated protein is selected from the group consisting of E2F1, HBP1, CDKN1A, NCOA3, ERa, PTEN, MECP2, HOXA5, VPS4B, MYCN, RAB 14, DPYSL2, TGFBR2, TSG101, ARHGAP12, BACE1, PDCD4, PTEN, RECK, PPARa, TFMP3, FasL, TGFBR2, SERINB5, CDK2AP1, TPMl, CDKNIB, KIT, PPP2R2A, p27kipl, CDKN1C, ERa, KIT, DDIT4, BNIP3L, ZEB2, TBK1, CREBZF, MYBL1, DKK2, NIRF, NF2, CASP3, TRJM71, BACE1, DMTF1, C22orf5, BCL2, ARL2, CCNT2, TPPP3, VEGFA, RARS, FGF2, ZNF622, DNAJB4, PURA, SHOC2, LUZP1, FNDC3B, ITGA2, ATG9A, CA12, TMEM43, YIF1B, TMEM189, VTI1B, RTN4, TOMM34, NAA15, PNP, SRPR, IP04, NAPg, PFAH1B2, SLC12A2, SEC24A, NOTCH2, PPP2R5C, KCNN4, UBE4A, KPN A3, RAB30, ACP2, SRPRB, EIF4E, ABCF2, TPM3, ARHGDIA, GALNT7, LYPLA2, CHORDC1, TMEM109, LAMC1, EGFR, GPAM, ADSS, PPIF, RFTl, TNFSF9, IGF2R, TXN2, GFPTl, SLC7A1, SQSTMl, PANXl, UTP15, NPR3, SLC16A3, PTGS2, HARS, LAMTOR3, HSPA1B, ZEB1, CTNNB1, BAPl, GEMIN2, PTPRD, WDR37, KLFl l, SEPT9, HOXB5, ERBB2IP. KLHL20, FOG2, RIN2, RASSF2, ELM02, TCF7L1, VAC 14, SHC1, SEPT7, FOG2, SIRTl, BCL2, YY1, MYC, CDK6, CCNDl, FOXP1, HNF4a, CDKN2C, ACSL4, LEF1, ACSL 1, MTA2, AXL, LDHA, HDACl, CD44, BCL2, E2F3, SIRTl, BCL2, CCNDl, NMYC, MDM2, IGF-1, DHFR, MYC, CDK4, OCT4, SOX2, KRAS, ELK1, KLF4, MCL1, CCNE1, CDK6, HDACl, p85a, CDC42, and Cyclin Gl .

11. The method of claim 9, wherein the microparticle is transfected with exogenous microRNA.

12. The method of claim 1 1, wherein the microRNA is selected from the group consisting of miR-34, miR-192, miR-145, miR-143, miR-16-l„ miR125b, miR-30, miR-128, miR-504, miR380, miR-33, miR-25, miR-449, miR-215, miR605, miR-29, miR-17-92, miR- 21, let-7, miR-15/16, miR-200 and miR-34.

13. The method of claim 9, wherein the cancer is selected from the group consisting of: breast cancer, lung cancer, colorectal cancer, pancreatic cancer, head and neck cancer, brain cancer, melanoma, skin cancer, prostate cancer, thyroid cancer, kidney cancer and bladder cancer.

14. A composition comprising a Wharton's Jelly cell derived microparticle and exogenous microRNA.

15. The composition of claim 14, wherein the exogenous microRNA downregulates a cancer associated protein.

16. The composition of claim 14, wherein the microRNA is selected from the group consisting of miR-34, miR-192, miR-145, miR-143, miR-16-l„ miR125b, miR-30, miR-128, miR-504, miR380, miR-33, miR-25, miR-449, miR-215, miR605, miR-29, miR-17-92, miR- 21, let-7, miR-15/16, miR-200 and miR-34.

17. A kit for the downregulation of a cancer associated protein comprising a Wharton's Jelly cell derived microparticle and instructions for use.

18. The kit of claim 17, wherein the microparticle is transfected with exogenous microRNA.

19. The kit of claim 18, wherein the microRNA is selected from the group consisting of miR-34, miR-192, miR-145, miR-143, miR-16-l„ miR125b, miR-30, miR-128, miR-504, miR380, miR-33, miR-25, miR-449, miR-215, miR605, miR-29, miR-17-92, miR-21, let-7, miR-15/16, miR-200 and miR-34.

20. The kit of claim 17, wherein the cancer associated protein is selected from the group consisting of E2F1, HBP1, CDKN1A, NCOA3, ERa, PTEN, MECP2, HOXA5, VPS4B, MYCN, RAB 14, DPYSL2, TGFBR2, TSG101, ARHGAP12, BACE1, PDCD4, PTEN, RECK, PPARa, TJJVIP3, FasL, TGFBR2, SERINB5, CDK2AP1, TPMl, CDKNIB, KIT, PPP2R2A, p27kipl, CDKNIC, ERa, KIT, DDIT4, BNIP3L, ZEB2, TBKl, CREBZF, MYBL1, DKK2, NIRF, NF2, CASP3, TRJM71, BACE1, DMTF1, C22orf5, BCL2, ARL2, CCNT2, TPPP3, VEGFA, RARS, FGF2, ZNF622, DNAJB4, PURA, SHOC2, LUZP1, FNDC3B, ITGA2, ATG9A, CA12, TMEM43, YIF1B, TMEM189, VTI1B, RTN4, TOMM34, NAA15, PNP, SRPR, IP04, NAPg, PFAH1B2, SLC12A2, SEC24A, NOTCH2, PPP2R5C, KCNN4, UBE4A, KPN A3, RAB30, ACP2, SRPRB, EIF4E, ABCF2, TPM3, ARHGDIA, GALNT7, LYPLA2, CHORDC1, TMEM109, LAMC1, EGFR, GPAM, ADSS, PPIF, RFTl, T FSF9, IGF2R, TXN2, GFPTl, SLC7A1, SQSTMl, PANXl, UTP15, NPR3, SLC16A3, PTGS2, HARS, LAMTOR3, HSPA1B, ZEB1, CTNNB1, BAPl, GEMIN2, PTPRD, WDR37, KLFl l, SEPT9, HOXB5, ERBB2IP. KLHL20, FOG2, RIN2, RASSF2, ELM02, TCF7L1, VAC 14, SHCl, SEPT7, FOG2, SIRTl, BCL2, YYl, MYC, CDK6, CCNDl, FOXP1, HNF4a, CDKN2C, ACSL4, LEF1, ACSL 1, MTA2, AXL, LDHA, HDACl, CD44, BCL2, E2F3, SIRTl, BCL2, CCNDl, NMYC, MDM2, IGF-1, DHFR, MYC, CDK4, OCT4, SOX2, KRAS, ELK1, KLF4, MCL1, CCNEl, CDK6, HDACl, p85a, CDC42, and Cyclin Gl .