AU2012298794A1

AU2012298794A1 - Biomarkers predictive of therapeutic responsiveness to HSP90 inhibitors and uses thereof

Info

Publication number: AU2012298794A1
Application number: AU2012298794A
Authority: AU
Inventors: Christian Fritz; John J. Keilty; Jeffery L. Kutok; Juan Guillermo Paez
Original assignee: Infinity Pharmaceuticals Inc
Current assignee: Infinity Pharmaceuticals Inc
Priority date: 2011-08-23
Filing date: 2012-08-23
Publication date: 2013-04-04
Also published as: WO2013028907A1

Abstract

Methods, assays and kits for identifying, assessing and/or treating a cancer responsive to a treatment that includes an HSP90 inhibitor in combination with a taxane are disclosed.

Description

12041-7037WO / 1014 WO BIOMARKERS PREDICTIVE OF THERAPEUTIC RESPONSIVENESS TO HSP90 INHIBITORS AND USES THEREOF 5 RELATED APPLICATIONS This application claims priority to U.S. Application Serial No. 61/526,471, filed August 23, 2011, the entire content of which is hereby incorporated herein by reference. BACKGROUND 10 Heat shock protein (Hsp or HSP) 90 belongs to a family of proteins induced by a variety of cell stresses, e.g., heat, nutrient depletion, and ambient acidity. Hsps serve as multicomponent machines, "chaperones," that assist in the proper folding of newly synthesized proteins or refolding of proteins damaged by heat or other stresses, termed "clients" (Ciocca, D. R. and Calderwood, S. K. (2005) Cell Stress & 15 Chaperones, 10(2):86-103; Kamal et al. (2004) Clin Cancer Res, 10:4813-4821). Hsp90 is involved in protein homeostasis and regulates the stability of key proteins involved in oncogenesis, cell proliferation, and survival through its role as a protein chaperone (Whitesell L. et al. (2005) Nat Rev Cancer, 5(10):761-772). Over 500 Hsp90 client proteins have been identified, including hormone receptors, such as 20 estrogen receptor (ER), progesterone receptor (PR), glucocorticoide receptor (GR); oncogene products (e.g., c-erbB2, bcr-abl, npm-alk, c-raf, and v-src); regulators of cancer cell growth and cell cycle progression (e.g., cdk4, EGF-R, IGF1-R, and telomerase); and apoptosis-related signaling (e.g., akt, mutant p53) (Kamal et al. (2004) supra; Pratt, W.B. and Toft, D.O. (2003) Expfiol Med, 228(2):111-33). 25 Hsp90 exists in two major isoforms, Hsp90x and Hsp90. Biochemical and functional differences, as well as differences in the expression mechanisms and induction of the two isoforms are known (Ciocca, D. R. and Calderwood, S. K. (2005) supra; Sreedharet al. (2004) FEBS Letter, 562:11-15; Picard, D. (2004) Nature Cell Biol., 6:479-480). Hsp90x is encoded by 10 exons in a 5.33 kb genomic DNA, and 30 Hsp90 is encoded by 11 exons in a 6.88 kb DNA stretch. The human isoforms are about 85% homologous and share a common N-terminal ATP- and geldanamycin binding site (Sreedharet al. (2004) supra). Their middle domain is the site of client - 1 - 12041-7037WO / 1014 WO protein binding, and the C-terminal domain is responsible for binding co-chaperone molecules (Sreedharet al. (2004) supra). Evidence has emerged that Hsp90x and are differently expressed in tumors (Ciocca, D. R. and Calderwood, S. K. (2005) supra; Sreedharet al. (2004) supra; Picard (2004) supra; Eustace et al. (2004) Nature 5 Cell Biol., 6:507-514). SUMMARY The present disclosure provides, at least in part, methods, assays, and kits for identifying, assessing and/or treating a cancer responsive to a treatment that comprises 10 an HSP90 inhibitor (e.g., a treatment that includes an HSP90 inhibitor in a combination, e.g., in combination with another chemotherapeutic agent provided herein, such as a taxane). In one embodiment, the responsiveness of a subject to an HSP90 inhibitor in combination with a chemotherapeutic agent, e.g., a taxane, is evaluated by determining the level of HSP90x in the subject (e.g., in a sample, e.g., a 15 tissue, a blood, a plasma, or a serum sample, obtained from the subject). In certain embodiments, an increased level of circulating HSP90x relative to a predetermined value is indicative of increased responsiveness to treatment and/or longer survival (e.g., overall survival and/or progression free survival), when the subject, e.g., a cancer patient (e.g., a patient with a lung cancer), is evaluated prior to, during, or after 20 the HSP90 inhibitor combination therapy. Thus, levels of circulating HSP90x can be used as a predictive and/or a prognostic biomarker of a cancer therapy that includes HSP90 inhibition. For example, levels of circulating HSP90x can be used to evaluate responsiveness to, or to monitor, a therapy that comprises an HSP90 inhibitor; to identify a patient as likely 25 to benefit from such therapy; to stratify a patient population (e.g., to classify patients as being likely or less likely to respond) to a therapy that comprises an HSP90 inhibitor; to predict a time course of disease or a probability of a significant event in the disease of such subjects (e.g., increased or decreased patient survival), and/or to more effectively monitor or treat the cancer. In certain embodiments, levels of 30 circulating HSP90x can be used in combination with one or more other markers provided herein (e.g., a marker for hypoxia) as predictive and/or prognostic biomarkers of a cancer therapy. -2- 12041-7037WO / 1014 WO Accordingly, in one aspect, provided herein is a method of, or an assay for, evaluating a subject, e.g., a subject with a cancer, e.g., a subject with lung cancer (e.g., non-small cell lung cancer (NSCLC)), for example, based on a sample (e.g., a tissue, a blood, a plasma, or a serum sample) obtained from the subject. In one 5 embodiment, the method, or assay, comprises determining the level (e.g, circulating or tissue level) of HSP90x in the subject, e.g., in a sample obtained from the subject. In one embodiment, the method, or assay, can further include one or more of the following: (1) identifying a subject as more likely or less likely to respond to a treatment comprising an HSP90 inhibitor, e.g., an HSP90 inhibitor in combination 10 with a chemotherapeutic agent (e.g., a taxane), based on the level (e.g, circulating level) of HSP90x in the subject, e.g., in a sample (e.g., a tissue, a blood, a plasma, or a serum sample) obtained from the subject; (2) selecting one or more subject(s) to be treated with a particular treatment regimen, e.g., an HSP90 inhibitor in combination with a chemotherapeutic agent (e.g., a taxane), based on the level of HSP90X in the 15 subject(s), (3) selecting a particular treatment regimen for a subject, based on the level of HSP90x in the subject; (4) prognosticating the time course of the disease in the subject (e.g., evaluating the likelihood of patient survival); and/or (5) treating the subject with an HSP90 inhibitor, e.g., in combination with one or more chemotherapeutic agent(s) (e.g., a taxane). 20 In one embodiment, an increased (or high) level of circulating HSP90 in a subject, e.g., in a sample obtained from the subject, relative to a predetermined value (e.g., the level of HSP90x in a subject that is greater than a predetermined value) is indicative or predictive of an increased responsiveness of the subject to a particular treatment comprising an HSP90 inhibitor (e.g., an HSP90 inhibitor in combination 25 with a chemotherapeutic agent, such as a taxane). In one embodiment, an increased responsiveness in a first subject having an increased (or high) level of circulating HSP90x to a treatment is relative to the responsiveness detected in a second subject, or group of subjects, having a lower level of HSP90x. In one embodiment, an increased responsiveness of a subject to a treatment or 30 an increased likelihood of a response to a treatment can include an increased tumor responsiveness and/or increased survival of the subject. In one embodiment, an increase in tumor responsiveness includes, but is not limited to, shrinkage of a tumor and/or decreased growth of a tumor. In one embodiment, an increased survival of a -3- 12041-7037WO / 1014 WO subject includes, but is not limited to, improved overall survival and/or progression free survival. In another embodiment, an increased (or high) level of circulating HSP90X in a subject, relative to a predetermined value, is indicative of longer patient survival, 5 e.g., when the subject is initiating, undergoing, or after undergoing, a combination therapy comprising an HSP90 inhibitor and a chemotherapeutic agent, such as a taxane. In one embodiment, an increased survival in a first subject having the increased (or high) HSP90ax level is relative to the survival detected in a second subject, or group of subjects, having a lower level of HSP90X. 10 In one embodiment, the level of circulating HSP90x in a subject correlates inversely to the level of tissue HSP90x (e.g., in a tumor tissue) in the subject (e.g., a subject having NSCLC). For example, a high level of circulating HSP90X in a subject corresponds to a low level of tissue HSP90x in the subject; and conversely, a low level of circulating HSP90x in a subject corresponds to a high level of tissue 15 HSP90x in the subject. In one embodiment, a biomarker described herein relate to the level of circulating HSP90x in a subject (e.g., in a whole blood, a serum, or a plasma sample of the subject). In other embodiment, a biomarker described herein relate to the level of tissue HSP90x in a subject (e.g., in a tumor tissue of the subject). Accordingly, in one embodiment, a low level of tissue HSP90X in a subject, 20 relative to a predetermined value, is indicative of an increased responsiveness of the subject to a particular treatment comprising an HSP90 inhibitor (e.g., an HSP90 inhibitor in combination with a chemotherapeutic agent, such as a taxane). In one embodiment, an increased responsiveness in a first subject having a low level of tissue HSP90x to a treatment is relative to the responsiveness detected in a second subject, 25 or group of subjects, having a higher level of tissue HSP90X. In one embodiment, a low level of tissue HSP90x in a subject, relative to a predetermined value, is indicative of longer patient survival, e.g., when the subject is initiating, undergoing, or after undergoing, a combination therapy comprising an HSP90 inhibitor and a chemotherapeutic agent, such as a taxane. In one embodiment, an increased survival 30 in a first subject having a low level of tissue HSP90x is relative to the survival detected in a second subject, or group of subjects, having a higher level of tissue HSP90x. -4- 12041-7037WO / 1014 WO In a related aspect, provided herein is a method of, or an assay for, determining the responsiveness of, a subject having a cancer, to a treatment comprising an HSP90 inhibitor (e.g., a treatment comprising an HSP90 inhibitor in combination with a chemotherapeutic agent, e.g., in combination with a taxane). In 5 one embodiment, the method comprises evaluating a subject (e.g., a sample from the subject), e.g., to determine the level (e.g, circulating or tissue level) of HSP90x, and (optionally) identifying or selecting the subject having the cancer as being more likely or less likely to respond to a treatment comprising an HSP90 inhibitor (e.g., an HSP90 inhibitor in combination with a taxane). In certain embodiments, the method 10 comprises the step of identifying or selecting one or more subject(s) (e.g., a patient, a patient group or population) with cancer (e.g., a patient with lung cancer (e.g., NSCLC)) as having an increased or decreased likelihood to respond to a treatment comprising an HSP90 inhibitor (e.g., an HSP90 inhibitor in combination with a taxane). 15 In one embodiment, an increased (or high) level (e.g, circulating level) of HSP90x in a subject, e.g., in a sample from the subject, relative to a predetermined value is indicative or predictive of increased responsiveness to a therapy comprising an HSP90 inhibitor in combination with a taxane. In one embodiment, an increased responsiveness in a first subject having an 20 increased (or high) HSP90x level (e.g, circulating level) is relative to the responsiveness detected in a second subject, or group of subjects, having a lower level of HSP90x. In another aspect, provided herein is a method of, or an assay for, evaluating or monitoring a treatment regimen in one or more subject(s) (e.g., a patient, a patient 25 group or population) having a cancer or at risk of developing a cancer (e.g., a subject having a lung cancer (e.g., NSCLC)). The method comprises evaluating the subject, (e.g., a sample from the subject), e.g., to determine the level (e.g, the circulating or tissue level) of HSP90x; and (optionally) selecting or altering one or more of: the therapy being administered to the subject; the course of therapy; dosing; treatment 30 schedule or time course; or the use of alternative therapies. In one embodiment, the method comprises comparing the level of HSP90x in a subject (e.g., in a sample obtained from the subject) to a predetermined value. The method can be used, e.g., to evaluate the suitability of a treatment, or to choose between alternative treatments, -5- 12041-7037WO / 1014 WO e.g., a particular dosage, mode of delivery, time of delivery, or generally to determine the subject's probable drug response. In one embodiment, an increased (or high) level (e.g, circulating level) of HSP90x in a subject, e.g., in a sample obtained from the subject, relative to a 5 predetermined value is indicative that a therapy comprising an HSP90 inhibitor in combination with a taxane is to be initiated or continued. In another embodiment, a decreased (or low) level (e.g, circulating level) of HSP90x in a subject, e.g., in a sample obtained from the subject, relative to a predetermined value is indicative of decreased responsiveness to a therapy comprising an HSP90 inhibitor in combination 10 with a taxane (e.g., as compared to the responsiveness of a subject having a higher level of HSP90x), and/or is indicative that a therapy comprising an HSP90 inhibitor in combination with a taxane should be combined with one or more additional therapies. In another embodiment, an increased (or high) level (e.g, circulating level) of 15 HSP90x in a subject relative to a predetermined value is indicative of longer patient survival, e.g., when the subject is initiating, undergoing, or after undergoing, a combination therapy comprising an HSP90 inhibitor and a taxane. In one embodiment, the increased survival in a first subject having an increased HSP90x level is relative to the survival detected in a second subject, or group of subjects, 20 having a lower level of HSP90x. In yet another aspect, provided herein is a method of, or an assay for, evaluating a time course of disease progression, in one or more subject(s) (e.g., a patient, a patient group or population), having a cancer, or at risk of developing a cancer (e.g., a subject having or at risk of having a lung cancer, e.g., NSCLC). The 25 method comprises evaluating the subject (e.g., a sample from the subject), e.g., to determine the level (e.g, circulating or tissue level) of HSP90x; and (optionally) comparing the level of HSP90x to a predetermined value. In one embodiment, an increased (or high) level (e.g, circulating level) of HSP90x relative to a predetermined value indicates an increased responsiveness of the subject to a therapy comprising an 30 HSP90 inhibitor in combination with a chemotherapeutic, e.g., a taxane, and/or the need for an HSP90 inhibition combination therapy. Conversely, a decreased (or low) level (e.g, circulating level) of HSP90x relative to a predetermined value indicates a decreased responsiveness of the subject (e.g., as compared to the responsiveness of a -6- 12041-7037WO / 1014 WO subject having a higher level of HSP90x) to a therapy comprising an HSP90 inhibitor in combination with a chemotherapeutic, e.g., a taxane. In another embodiment, an increased (or high) level of circulating HSP90x relative to a predetermined value is indicative of longer patient survival, e.g., when 5 the subject is undergoing a combination therapy comprising an HSP90 inhibitor and a taxane. Alternatively, or in combination with, the methods or assays described herein, provided herein is a method which comprises inhibiting, reducing, or treating a cancer, e.g., a lung cancer (e.g., a NSCLC), in a subject. In one embodiment, the 10 method comprises administering to the subject an HSP90 inhibitor (e.g., one or more HSP90 inhibitor(s) as described herein), as a single agent, or in a combination, e.g., in combination with a chemotherapeutic agent, such as a taxane (e.g., docetaxel or paclitaxel), in an amount sufficient to reduce, inhibit, or treat the cancer, in the subject. In one embodiment, after a determination of an increased (or high) level of 15 HSP90x in a subject relative to a predetermined value, an HSP90 inhibitor, alone or in combination with a chemotherapeutic agent, such as a taxane, is administered to the subject. In one embodiment, the chemotherapeutic agent used in combination with an HSP90 inhibitor in a method provided herein is an anti-cancer agent (e.g., a taxane or other anti-cancer agents known in the art). 20 In yet another aspect, the method or assay provided herein optionally further comprises the step of measuring one or more additional biomarker(s), in addition to HSP90x, e.g., to select a subject for a particular treatment, to select a treatment regimen for a particular subject, to adjust the treatment regimen of a treated subject, or to monitor the efficacy of a particular treatment in a treated subject. Such 25 additional biomarkers include, but are not limited to, a marker for hypoxia (e.g., hypoxia-inducible factor (HIF), or lactate dehydrogenase (LDH), among others), a marker involving a "client" protein for HSP90 (e.g., c-Kit, HER2, Akt-1, EGFR, Bcr Abl, PDGFR-x, among others), a histology biomarker, a tissue-based biomarker, a proteomic biomarker, and/or other oncogene markers (e.g., K-Ras, N-Ras, ALK, B 30 Raf, MEK1, P13K, etc.). In one embodiment, the method or assay provided herein optionally further comprises the step of measuring one or more marker(s) for hypoxia in a subject, such as, e.g., HIF or LDH, among others. See, e.g., WO 2012/068487, which is incorporated herein by reference. In certain embodiments, a high level of -7- 12041-7037WO / 1014 WO HSP90x in a subject in combination with a high level of hypoxia is indicative of increased responsiveness to a therapy described herein (e.g., a combination therapy comprising an HSP90 inhibitor and a taxane). In other embodiments, the biomarker(s) provided herein can be used in 5 combination with other classification(s) of disease or patients (e.g., in lung cancer patients, classification based on history of smoking, such as non-smokers, previous smokers, current smokers, heavy smokers, etc.), or in combination with a particular type or sub-type (e.g., squamous cell carcinoma or adenocarcinoma) or a particular stage of cancer (e.g., Stage I, III, III, IV of NSCLC). 10 Additional embodiments or features of the present disclosure are as follows: In certain embodiments, the methods or assays described herein further comprise one or more of the following: (i) evaluating the subject's K-Ras status, e.g., determining if the subject has an alteration (e.g., a mutant or wild type) K-Ras gene or gene product; 15 (ii) evaluating the subject's histology, e.g., detecting the presence of a cancerous histology, e.g., determining the histologic subtype of a NSCLC (e.g., adenocarcinoma or squamous cell carcinoma (SCC)), e.g., the presence of a solid tumor, or a metastatic lesion (e.g., detecting the presence of adenocarcinoma or squamous cell carcinoma cells or tissues in the subject's sample); 20 (iii) determining the subject's smoking status (e.g., never smoked, previous smoker, current smoker, and/or the extent of smoking history in pack years (packs smoked per day multiplied by years as a smoker, e.g., determining that the subject has a smoking history of at least 5, 10, 15, or more pack years); (iv) detecting if the subject has an alteration (e.g., one or more oncogenic 25 alterations) in an ALK, a MAPK pathway, and/or an EGFR gene or gene product; (v) detecting if the subject has an alteration (e.g., one or more oncogenic alterations) in a p53 gene product; (vi) detecting if the subject has an alteration in copy number for the 14q31-33 gene locus; 30 (vii) evaluating the subject's LKB1 status, e.g., determining if the subject has an alteration (e.g., a mutant or wild type) in LKB 1 gene or gene product; -8- 12041-7037WO / 1014 WO (viii) evaluating the subject's Raf status (e.g., B-Raf), e.g., determining if the subject has an alteration (e.g., a mutant or wild type) in B-Raf gene or gene product; and/or (ix) detecting the level of hypoxia in a tumor and/or detecting the level of a 5 hypoxia marker (e.g., LDH or HIF) in the subject or in a tumor sample derived from the subject. In one embodiment, the methods or assays described herein can, optionally, further comprise detecting an alteration in one or more gene products, such as, e.g., ALK, RAS, EGFR, PIK3CA, RAF, PTEN, AKT, TP53 (p53), CTNNB 1 (beta 10 catenin), APC, KIT, JAK2, NOTCH, FLT3, MEK, ERK, RSK, ETS, ELK-1, SAP-1, CDKN2a, KEAP1, NFE2L2, HLA-A, p13K, ErbB-2, CDK, DDR2, PDGFR, FGFR, retinoblastoma 1, or cullin 3. In one embodiment, the biomarker gene or gene product, e.g., cDNA, RNA (e.g., mRNA), or polypeptide can be evaluated using any of the methods described herein and in WO 2011/060328, incorporated herein by 15 reference. In other embodiments, an increased (or high) level of HSP90x in a subject, and one or more of the following is indicative of an increased likelihood to respond to a treatment comprising an HSP90 inhibitor (e.g., a treatment comprising a combination of an HSP90 inhibitor and a taxane): 20 (i) detecting the presence of a cancerous histology (e.g., adenocarcinoma and/or squamous cell carcinoma cells or tissue in the subject's histology); (ii) identifying the subject as a smoker (e.g., a subject who has a smoking history of at least 5, 10, 15, or more pack years); (iii) detecting the presence of wild type or mutant Ras gene or gene product 25 (in certain embodiments, wild type K-Ras is detected); (iv) detecting the presence of an alteration in an ALK gene or gene product (e.g., an ALK rearrangement); (v) detecting the presence of an alteration in a Raf, e.g., a B-Raf, gene or gene product; 30 (vi) detecting an alteration in copy number for the 14q31-33 gene locus; (vii) detecting the presence of wild type or mutant LKB 1 gene or gene product (in certain embodiments, a mutant LKB 1 is detected); and/or -9- 12041-7037WO / 1014 WO (viii) detecting the level of hypoxia in a tumor and/or detecting the level of a hypoxia marker (e.g., LDH or HIF-la) in the subject or in a tumor sample derived from the subject that is indicative of the level of hypoxia (in certain embodiments, a high level of hypoxia is detected). 5 In other embodiments of the methods or assays provided herein, the presence of an increased level of HSP90x in a subject, and one or more biomarkers chosen from an ALK, a MAPK pathway, and/or an EGFR gene or gene product is indicative that the subject has an increased likelihood to respond to a treatment comprising an HSP90 inhibitor in combination with a taxane. In certain embodiments, the MAPK 10 pathway gene or gene product includes Ras (e.g., one or more of H-Ras, N-Ras, or K Ras), Raf (e.g., one or more of A-Raf, B-Raf (BRAF) or C-Raf), Mek, and/or Erk. For any of the methods or assays disclosed herein, the subject treated, or the subject from which the sample is obtained, is a subject having, or at risk of having, a cancer at any stage of treatment. In certain embodiments, the cancer is chosen from 15 lung cancer, pancreatic cancer, melanoma, or salivary gland cancer. In other embodiment, the lung cancer is chosen from one or more of the following: non-small cell lung cancer (NSCLC), small cell lung cancer (SCLC), squamous cell carcinoma (SCC), adenocarcinoma, or bronchogenic carcinoma, or a combination thereof. In one embodiment, the cancer being treated is NSCLC (e.g., relapsed and/or refractory 20 NSCLC). In one embodiment, the cancer (e.g., NSCLC) being treated is at a certain stage (e.g., Stage IA, IB, IIA, JIB, IIIA, IIIB, or IV). In one embodiment, the NSCLC being treated is Stage IIIB or Stage IV NSCLC. In one embodiment, the cancer being treated is a particular type of lung cancer described herein. In one embodiment, the cancer being treated is squamous cell carcinoma of the lung. In one embodiment, the 25 cancer being treated is adenocarcinoma of the lung. In particular embodiments, the methods provided herein relate to treatment of certain types of NSCLC, including but not limited to, (1) squamous cell carcinoma, including but not limited to, papillary, clear cell, small cell, and basaloid carcinoma; (2) adenocarcinoma, including but not limited to, acinar, papillary, bronchioloalveolar 30 carcinoma (nonmucinous, mucinous, mixed mucinous and nonmucinous or indeterminate cell type), solid adenocarcinoma with mucin, adenocarcinoma with mixed subtypes, and other variants including well-differentiated fetal adenocarcinoma, mucinous (colloid) adenocarcinoma, mucinous cystadenocarcinoma, - 10 - 12041-7037WO / 1014 WO signet ring adenocarcinoma, and clear cell adenocarcinoma; (3) large cell carcinoma, including but not limited to, large cell neuroendocrine carcinoma, combined large cell neuroendocrine carcinoma, basaloid carcinoma, lymphoepithelioma-like carcinoma, clear cell carcinoma, and large cell carcinoma with rhabdoid phenotype; 5 (4) adenosquamous carcinoma; (5) carcinomas with pleomorphic, sarcomatoid, or sarcomatous elements, including but not limited to, carcinomas with spindle and/or giant cells, spindle cell carcinoma, giant cell carcinoma, carcinosarcoma, and pulmonary blastoma; (6) carcinoid tumor, including but not limited to, typical carcinoid and atypical carcinoid; (7) carcinomas of salivary-gland, including but not 10 limited to, mucoepidermoid carcinoma and adenoid cystic carcinoma; and (8) unclassified carcinoma. In one embodiment, the NSCLC treated herein is in the primary tumor, lymph nodes, and/or distant metastasis. Particular embodiments herein provide methods of treating NSCLC in a subject having surgically resectable NSCLC, locally or regionally advanced NSCLC, and/or distant metastatic NSCLC. 15 In one embodiment, the methods comprise treating certain stages of NSCLC, including but not limited to, occult carcinoma, Stage 0, Stage IA, Stage IB, Stage IIA, Stage JIB, Stage IIIA, Stage IIIB, and Stage IV. The staging of NSCLC can be defined according to methods known in the art, for example, according to the guidelines provided by the American Joint Committee on Cancer (AJCC). In one 20 embodiment, the staging of NSCLC is designated and grouped based on the TNM classification, i.e., a classification based on the status of primary tumor (e.g., TX, TO, Tis, Ti, T2, T3, T4), regional lymph nodes (e.g., NX, NO, Ni, N2, N3), and/or distant metastasis (e.g., MX, MO, M1), in a subject having NSCLC. In one embodiment, the subject being treated in a method described herein has 25 not been treated with other cancer therapy prior to receiving a treatment described herein. In other embodiments, the subject being treated in a method described herein has been treated with one or more other cancer therapies prior to receiving a treatment described herein. In one embodiment, the subject has one or more of the following: 30 (i) has a wild type K-Ras gene; (ii) is a smoker (e.g., a subject who has a smoking history of at least 5, 10, 15, or more pack years); - 11 - 12041-7037WO / 1014 WO (iii) has a certain cancerous histology (e.g., adenocarcinoma and/or squamous cell carcinoma cells or tissue in the subject's histology, e.g., adenocarcinoma and/or squamous cell carcinoma in a subject having NSCLC); (iv) has an alteration (e.g., one or more oncogenic alterations) in the p53 gene 5 product; (v) has an alterations in copy number for the 14q31-33 gene locus; (vi) has a mutant LKB 1 gene; (vii) has a mutant B-Raf gene; (viii) has a mutant ALK gene; and/or 10 (ix) has a high level of hypoxia in a tumor. Predetermined Values In certain embodiments, the level (e.g, circulating or tissue level) of HSP90x in a subject is compared to a predetermined value. In some embodiments, an 15 increased (or high) level (e.g, circulating level) of HSP90x in a sample from a subject is indicative of increased responsiveness to a treatment comprising an HSP90 inhibitor in combination with a taxane. In some embodiments, increased responsiveness is a better response and/or increased likelihood of a better response, as assessed, e.g., based on tumor responsiveness (e.g., % change in tumor size relative to 20 baseline or relative to an appropriate control), and/or based on survival (e.g., overall survival and/or progression free survival). In one embodiment, the predetermined value is a reference or control value or sample; a middle value (e.g., a median value) of HSP90x in a reference group (e.g., a group of patients or healthy controls); the value in a sample obtained from a healthy 25 subject; the value in a sample obtained from a patient; or the value in a sample obtained from a subject at a different time interval (e.g., prior to, during, at various time points after the completion of the course of a treatment to monitor the treatment, and/or adjust dose or treatment regimen). In one embodiment, the sample is obtained prior to treatment with the HSP90 30 inhibitor and the taxane. In another embodiment, the sample is obtained during treatment with the HSP90 inhibitor and the taxane. In yet another embodiment, the sample is obtained after treatment with the HSP90 inhibitor and the taxane. - 12 - 12041-7037WO / 1014 WO In one embodiment, a middle (e.g., a median value of HSP90X) is determined from a patient group afflicted with the same or a different cancer. In another embodiment, a median value as identified in the Examples is used. In some embodiments, the level of HSP90x in a subject, e.g., a sample from 5 the subject, and/or the predetermined value is normalized. The level can be normalized relative to any appropriate control value as known in the art or as described herein. In some embodiments, the normalization is relative to a level of HSP90x in a different sample(s) (e.g., sample(s) taken at an earlier time-point) from the same subject or from the same group of subjects. In other embodiments, 10 normalization is relative to a level of a different protein (e.g., albumin) as determined in the same sample or a different sample (e.g., a different sample from the same subject or from the same group of subjects). In further embodiments, the level is normalized relative to a measure of central tendency (e.g., a mean or median) in an appropriate reference group (e.g., a sample of patients with the same disease). The 15 normalization of values can be carried out by any means known in the art, including, e.g., a difference, ratio, or percentage. In some embodiments, the predetermined value is chosen from a median cutoff, an optimized cutoff, or a designated quartile. In one embodiment, an increased level of HSP90x in a subject (e.g., in a sample obtained from the subject, e.g., a 20 whole blood, serum, or plasma sample, from which the level of HSP90X is determined) is a level that is greater than, or equal to, the predetermined value (e.g., a value greater than, or equal to, the median cutoff, the optimized cutoff, or a higher percentage of the designated quartile). A median cutoff, an optimized cutoff, or a designated quartile can be 25 calculated based on a value obtained from a group of subjects. For example, the value can be calculated based, at least in part, on the HSP90X levels from a group of subjects that includes the subject from whom the sample (e.g., the plasma or serum sample) is obtained. Alternatively, the value can be calculated based, at least in part, on the HSP90x levels from a group of subjects that does not include the subject from 30 whom the sample (e.g., the plasma or serum sample) is obtained. The group of subjects can be, e.g., a reference group of subjects that has one or more of: the same disease (e.g., NSCLC), the same histology (e.g., squamous cell carcinoma or adenocarcinoma), the same stage of cancer (e.g., Stage IIIA, IIIB, or IV), the same - 13 - 12041-7037WO / 1014 WO KRAS mutant status (e.g., wild-type), the same LKB1 mutant status (e.g., LKB1 mutation), the same B-Raf mutant status (e.g., B-Raf mutation), the same ALK mutant status (e.g., ALK mutation), the same 14q31-33 mutation status (e.g., alternation in copy number for the 14q31-33 gene locus), a similar hypoxia status 5 (e.g., high hypoxia), and/or a similar history (e.g., in terms of individual characteristics, such as age, gender, medical history, and/or history as a smoker or nonsmoker, etc.). In some embodiments, the optimized cutoff is calculated by selecting the cutoff associated with the smallest p value for a particular test statistic (e.g., the log 10 rank test or hazard ratio). Further details pertaining to calculation of optimized cutoffs are described in Contal&O'Quigley (1999) Computational Statistics & Data Analysis, 30:253-270; Clark, G.M. et al. (2006) J. ThoracOncol., 1:837-846. Where applicable, a correction for multiple testing can be performed, for example, using the method of Schulgenet al. (1994) Am. J. Epidem., 140:172-184. 15 In specific embodiments, a predetermined value can be determined based on data values obtained from a group of subjects (e.g., a patient population having a certain disease), and using a method known in the art (e.g., Contal & O'Quigley (1999) supra, which is incorporated herein by reference). In some embodiments, the optimized cutoff value of Hsp90a is determined 20 using the same outcome variable as is being predicted. For example, the optimized cutoff value can be determined by optimizing the ability of the cutoff to predict tumor responsiveness and can subsequently be used to predict tumor responsiveness; or the optimized cutoff value can be determined by optimizing the ability of the cutoff to predict survival and can subsequently be used to predict survival. In other 25 embodiments, the optimized cutoff value of Hsp90a is determined using a different outcome variable than is being predicted. For example, the optimized cutoff value can be determined by optimizing the ability of the cutoff to predict tumor responsiveness and can subsequently be used to predict survival, or the optimized cutoff value can be determined by optimizing the ability of the cutoff to predict 30 survival and can subsequently be used to predict tumor responsiveness. In one embodiment, the designated quartile refers to a stratification of a group of subjects, e.g., a patient population, e.g., according to the value of HSP90aX levels. Exemplary designated quartiles include those subjects having HSP90ax levels - 14 - 12041-7037WO / 1014 WO corresponding to below the 25h percentile, equal to or greater than the 25th percentile but less than the 50h percentile, equal to or greater than the 50t percentile but less than the 7 5 th percentile, and equal to or greater than the 7 5 th percentile. In one embodiment, a decrease in target lesion size is detected as the HSP90X 5 level is increased (e.g., patients in a quartile having higher HSP90ax values have or are expected to have, a smaller lesion size after treatment). In one embodiment, a group of subjects, e.g., a patient population, is divided into quartiles, e.g., according to their HSP90ax levels. In one embodiment, subjects are selected for a particular therapy based on the quartile they belong to, or based on a percentile cutoff. 10 In one embodiment, a designated quartile can refer to the 25th percentile, the 50th percentile, or the 75th percentile. In one embodiment, the cutoff corresponds to above the 25th percentile, above the 50th percentile, or above the 75th percentile. In an exemplary embodiment, the cutoff corresponds to above the 25th percentile. In an exemplary embodiment, the cutoff corresponds to above the 50th percentile. In an 15 exemplary embodiment, the cutoff corresponds to above the 75th percentile. In other embodiments, a group of subjects can be stratified into other number of subgroups (besides into four quartiles), such as, e.g., stratified into two subgroups (e.g., cutoff at 50th percentile), three subgroups (e.g., cutoff at 33th or 67th percentile), or five subgroups (e.g., cutoff at 20t, 40t, 60t, or 8 0 th percentile). 20 In one embodiment, if the level of HSP90x of a subject (e.g., a cancer patient), prior to, during, or after, treatment with an HSP90 inhibitor is below a predetermined value, it is indicative of decreased likelihood of response to treatment with the HSP90 inhibitor in combination with a taxane, e.g., relative to the likelihood of response in a subject having a higher level of HSP90x. For example, if the level of circulating 25 HSP90x polypeptide in the plasma of a cancer patient (e.g., a patient with NSCLC) prior to, during, or after treatment is less than a predetermined value (e.g., a middle or median value of a group of subjects (e.g., patients or healthy controls); an optimized cutoff; or a value in a designated quartile corresponding to below the 25th percentile) (HSP90ax levels in this range are also referred to herein as "low circulating 30 HSP90x"), the cancer patient is less likely to respond to treatment with an HSP90 inhibitor in combination with a taxane, e.g., as compared to the response of a subject having a higher level of HSP90x. In such embodiments, the cancer patient can show an increase, after treatment, in the cancerous lesion (e.g., tumor size), e.g., an increase - 15 - 12041-7037WO / 1014 WO in lung tumor size of at least about 10%, 15%, 20%, 25%, 30%, 35%, or 40%, relative to a baseline level. It shall be noted that the subject having a lower level of HSP90x can respond favorably to treatment relative to an untreated subject (e.g., by showing a decreased level of cancerous lesion as compared to an untreated subject). 5 In other embodiments, a level of circulating HSP90x polypeptide in the plasma or serum of a cancer patient (e.g., a patient with NSCLC) prior to, during, or after treatment is about a predetermined value (e.g., a middle or median value of a group of subjects (e.g., patients or healthy controls); an optimized cutoff; or a value in a designated quartile corresponding to equal to, or greater than, the 2 5 th percentile, but 10 less than the 7 5 th percentile) (also referred to herein as "intermediate circulating HSP90x"), is indicative of a variable response to an HSP90 inhibitor in combination with a taxane. In such embodiments, the cancer patient can show an increase or a decrease, after treatment, in the cancerous lesion (e.g., tumor size), e.g., an increase or decrease in lung tumor size of about 1%, 5%, 10%, 15%, or 20%, relative to a 15 baseline level. In yet other embodiments, a level of circulating HSP90x polypeptide in the plasma or serum of a cancer patient (e.g., a patient with NSCLC) prior to, during, or after treatment is greater than a predetermined value (e.g., a middle or median value of a group of subjects (e.g., patients or healthy controls); an optimized cutoff; or a 20 value in a designated quartile corresponding to equal to or greater than the 7 5 th percentile) (HSP90x levels in this range are also referred to herein as "high circulating HSP90x"), is indicative of an increased likelihood to respond to treatment with an HSP90 inhibitor in combination with a taxane. In such embodiments, the cancer patient can show a decrease, after treatment, in the cancerous lesion (e.g., 25 tumor size), e.g., a decrease in lung tumor size of at least about 1%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, or 40%, relative to a baseline level. In other embodiments, if the level of circulating HSP90x polypeptide in the plasma or serum of a cancer patient (e.g., a patient with NSCLC) prior to, during, or after therapy with an HSP90 inhibitor is greater than a predetermined value (e.g., a 30 middle or median value of a group of subjects (e.g., patients or healthy controls); an optimized cutoff; or a value in a designated quartile corresponding to equal to or greater than the 75th percentile), the cancer patient has an increased probability of survival upon treatment with an HSP90 inhibitor administered in combination with a - 16 - 12041-7037WO / 1014 WO taxane. For example, the cancer patient can have an increased probability of survival of 10, 20, 50, 100, or more days relative to a subject having lower levels of HSP90X. Conversely, if the level of circulating HSP90x polypeptide in the plasma or serum of a cancer patient (e.g., a patient with NSCLC) prior to, during, or after therapy with an 5 HSP90 inhibitor is less than a predetermined value, the cancer patient (e.g., a patient with lung cancer, e.g., NSCLC) has a decreased probability of survival upon treatment with an HSP90 inhibitor administered in combination with a taxane (e.g., as compared to the probability of survival of a cancer patient having levels of HSP90x greater than the predetermined value). 10 In some embodiments, the sample (e.g., a whole blood, plasma, or serum sample) that is used to determine the level of HSP90x is non-hemolyzed or substantially non-hemolyzed (e.g., the sample does not show detectable hemolysis; the sample does not show statistically significant level of hemolysis; or the level of hemolysis in the sample is negligible, e.g., such that the level of hemolysis does not 15 appreciably influence the measured level of HSP90x). In some embodiments, the level of HSP90x in a sample obtained from a subject is corrected for hemolysis. In one embodiment, it is expected that a sample obtained from a subject will contain a variable amount of hemolysis, and hemolyzed red blood cells contain levels of HSP90x. Thus, the levels of hemolysis can be 20 extrapolated to specified levels of HSP90x across all subjects. In some embodiments, the sample (e.g., a whole blood, plasma, or serum sample) from which the level of HSP90x is determined is tested for hemolysis. In some embodiments, the extent of hemolysis and/or the level of Hsp90x that is derived from lysed red blood cells (RBC) in the sample is assessed using spectrophotometrical analysis (e.g., a 25 spectrophotometric optical density reading at 575 nm, as described herein). In some embodiments, the level of HSP90x in the sample is corrected for hemolysis, e.g., by subtracting the level of Hsp90x that is derived from lysed red blood cells in the sample from the total measured level of HSP90x in the sample (e.g., as assessed using spectrophotometric optical density readings on an ELISA plate, e.g., at 450 nm, as 30 described herein). In one embodiment, the method or assay includes comparing the level of HSP90x and/or other biomarker to a predetermined value, e.g., a predetermined value as described herein. For example, a sample can be analyzed at any stage of treatment, - 17 - 12041-7037WO / 1014 WO e.g., prior to, during, or after, administration of the HSP90 inhibitor, to thereby determine appropriate dosage and treatment regimen of the HSP90 inhibitor (e.g., amount per treatment or frequency of treatments). In certain embodiments, the methods, or assays, include the step of detecting the level of HSP90x and/or other 5 biomarker in the subject, prior to, or after, administering the HSP90 inhibitor, to the subject. In certain embodiments, a level of HSP90x in the sample (e.g., a serum or plasma sample) in the range of responsiveness described herein indicates that the subject from whom the sample was obtained is likely to be responsive to the HSP90 inhibitor. A level of HSP90x in the sample (e.g., a serum or plasma sample) in the 10 range of decreased responsiveness described herein indicates that the subject from whom the sample was obtained can respond to the HSP90 inhibitor to a lesser extent than a subject having a higher level of HSP90x. In yet another embodiment, HSP90x and/or other biomarker is assessed at predetermined intervals, e.g., a first point in time and at least at a subsequent point in 15 time. In one embodiment, a time course is measured by determining the time between significant events in the course of a patient's disease, wherein the measurement is predictive of whether a patient has a long time course. In another embodiment, the significant event is the progression from primary diagnosis to death. In another embodiment, the significant event is the progression from primary diagnosis to 20 metastatic disease. In another embodiment, the significant event is the progression from primary diagnosis to relapse. In another embodiment, the significant event is the progression from metastatic disease to death. In another embodiment, the significant event is the progression from metastatic disease to relapse. In another embodiment, the significant event is the progression from relapse to death. In certain embodiments, 25 the time course is measured with respect to one or more of overall survival rate, time to progression and/or using the RECIST or other response criteria. In one embodiment, the HSP90x and/or other biomarker is assessed in a cancer patient (e.g., a patient with a lung cancer, e.g., NSCLC) prior to administration of an HSP90 inhibitor described herein (e.g., prior to administration of an HSP90X 30 inhibitor). In one embodiment, HSP90x is assessed in a newly diagnosed cancer patient, e.g., a newly diagnosed lung cancer patient prior to therapy with an HSP90X inhibitor alone or in combination with a taxane. In another embodiment, the HSP90X and/or other biomarker is assessed in a cancer patient (e.g., a patient with lung cancer, - 18 - 12041-7037WO / 1014 WO e.g., NSCLC) after administration of an HSP90 inhibitor described herein (e.g., after administration of the HSP90 inhibitor for one week, two weeks, three weeks, one month, two months, three months, four months, six months, one year, or more). In certain embodiments, a predetermined measure or value is created after 5 evaluating the sample by dividing or stratifying the subject's samples into at least two patient subgroups (e.g., responders, less responders vs. non-responders). In certain embodiments, the number of subgroups is two, such that the patient sample is divided into a subgroup of patients having a specified level of HSP90X described herein, and a subgroup not having the specified level of HSP90x. In certain embodiments, 10 HSP90x status in the subject is compared to either the subgroup having or not having the specified level of HSP90x, if the lung cancer patient has a specified value, e.g., a level of the HSP90x, in the range of responsiveness described herein in the sample (e.g., a serum or plasma sample), then the lung cancer patient is likely to respond to treatment with an HSP90x inhibitor. 15 Alternatively, if the lung cancer patient has a predetermined value, e.g., a level of the HSP90x, in the range of decreased responsiveness described herein in the sample (e.g., a serum or plasma sample), then the lung cancer patient is likely to respond to treatment that includes the HSP90 inhibitor, to a lesser extent than a subject having a higher HSP90ax level. In certain embodiments, the number of 20 subgroups is greater than two, including, without limitation, three subgroups, four subgroups, five subgroups, and six subgroups, depending on stratification of predicted efficacy of an HSP90 inhibitor as correlated with the biomarkers described herein. It shall be understood that a decreased responsiveness to the HSP90 inhibitor taxane combination therapy and/or decreased survival detected in a subject having a 25 lower level of HSP90x is relative to a subject having a higher level of HSP90X, and not an untreated subject. Subjects having both high and low HSP90X can show increased responsiveness to the combination therapy and/or longer survival in response to a treatment that includes an HSP90 inhibitor and a taxane compared to an untreated subject. 30 Samples In certain embodiments, the method, or assay, further includes the step of obtaining the sample, e.g., a biological sample, from the subject. In one embodiment, - 19 - 12041-7037WO / 1014 WO the method, or assay, includes the step of obtaining a predominantly non-cellular fraction from the subject. The non-cellular fraction can be plasma, serum, or other non-cellular bodily fluid. In one embodiment, the sample is a serum or plasma sample. In other embodiments, the body fluid from which the sample is obtained 5 from an individual comprises blood (e.g., whole blood). In certain embodiments, the blood can be further processed to obtain plasma or serum. In another embodiment, the sample contains a tissue, or cells (e.g., tumor cells). For example, the sample can be a fine needle biopsy sample; an archival sample (e.g., an archived sample with a known diagnosis and/or treatment history); a histological section (e.g., a frozen or 10 formalin-fixed section, e.g., after long term storage), among others. A sample can include any material obtained and/or derived from a biological sample, including a polypeptide, and nucleic acid (e.g., genomic DNA, cDNA, RNA) purified or processed from the sample. Purification and/or processing of the sample can include one or more of extraction, concentration, antibody isolation, sorting, concentration, 15 fixation, addition of reagents and the like. In certain embodiments, the HSP90x is an HSP90x gene or gene product, e.g., cDNA, RNA (e.g., mRNA) or polypeptide. In one embodiment, the HSP90X detected is an HSP90x polypeptide, e.g., a human HSP90x polypeptide, or a fragment thereof. Exemplary human HSP90x amino acid and nucleotide sequences are provided herein 20 as SEQ ID NOs: 1, 3 and SEQ ID NOs:2, 4, respectively. In certain embodiments, the HSP90x is found extracellularly or circulating, e.g., circulating in the blood, serum or plasma of the subject. In embodiments where the HSP90x polypeptide is evaluated, the polypeptide can be detected, or the level determined, by any means of polypeptide detection, or 25 detection of the expression level of the polypeptide. For example, the polypeptide can be detected using a reagent which specifically binds with the HSP90X polypeptide. In one embodiment, the reagent is selected from the group consisting of an antibody, an antibody derivative, and an antibody fragment. In one embodiment, the HSP90X polypeptide is detected using, e.g., antibody-based detection techniques, such as 30 enzyme-based immunoabsorbent assay (e.g., ELISA), immunofluorescence cell sorting (FACS), immunohistochemistry, immunofluorescence (IF), western blot, affinity purification, fluorescence resonance energy transfer (FRET) imaging, antigen retrieval and/or microarray detection methods. In other embodiments, the HSP90x - 20 - 12041-7037WO / 1014 WO polypeptide is detected using mass spectrometry. In one embodiment, the detection, or determination of the level of the HSP90x polypeptide includes contacting the sample with a reagent, e.g., an antibody that binds to the HSP90X polypeptide, and detecting or determining the level of the reagent, e.g., the antibody, bound to the 5 HSP90x polypeptide. The reagent, e.g., the antibody, can be labeled with a detectable label (e.g., a fluorescent or a radioactive label, biotin-avidin detection). Polypeptide detection methods can be performed in any other assay format, including but not limited to, ELISA, RIA, and mass spectrometry. The amount, structure and/or activity of the HSP90x polypeptide can be compared to a predetermined value (e.g., a 10 reference or control value, e.g., a control sample). In one embodiment, the detection or determination step includes an enzyme-based immunoabsorbent assay. In such embodiments, the detection is usually driven by a fluorescent molecule bound to the detection antibody by biotin. In certain embodiments, the detection or determining steps of the methods or 15 assays described herein include determining quantitatively the level (e.g., amount or concentration) of HSP90x from a sample, e.g., a sample of plasma, serum, or other non-cellular body fluid; or a cellular sample (e.g., a tissue sample), wherein the amount or concentration of HSP90x thereby provides a value (also referred to herein as a "determined" or "detected" "value"). In certain embodiments, the determined or 20 detected value is compared to a predetermined value (e.g., a reference or control value; the value in a control sample; the value in a sample obtained from a subject or a group of subjects (e.g., healthy subjects or subjects afflicted with the disease; or the value in a sample obtained from the subject (or group of subjects) at different time intervals, e.g., prior to, during, or after treatment), to thereby evaluate, identify a 25 patient, or monitor treatment efficacy or a susceptibility thereto, and/or monitor response to an HSP90x therapy in an individual. In one embodiment, the sample is obtained prior to treatment with the HSP90 inhibitor and the taxane. In alternative embodiments, the sample is assayed for qualitative, or both quantitative and qualitative determination of the HSP90ax level. In certain embodiments, methods or 30 assays provided herein relate to determining quantitatively the amount or concentration of the HSP90x from plasma or serum of the subject, wherein the plasma or serum is obtained from the blood of the subject, for example. - 21 - 12041-7037WO / 1014 WO Treatment Alternatively, or in combination with the methods described herein, provided herein is a method of treating cancer (e.g., a lung cancer, e.g., NSCLC) in a subject. In one embodiment, the subject is previously identified as likely or unlikely to 5 respond to treatment with an HSP90 inhibitor, alone or in combination with a chemotherapeutic agent, such as a taxane, using the methods or assays described herein. In one embodiment, after determining an increased (or high) level of HSP90X relative to a predetermined value, the method comprises administering to a subject (e.g., a patient with lung cancer), an HSP90 inhibitor in combination with a taxane, in 10 an amount sufficient to reduce or inhibit the cancer cell growth, and/or to treat the cancer, in the subject. "Treatment" as used herein includes, but is not limited to, inhibiting tumor growth, reducing tumor mass, reducing size or number of metastatic lesions, inhibiting the development of new metastatic lesions, prolonged survival, prolonged 15 progression-free survival, prolonged time to progression, and/or enhanced quality of life. In certain embodiments, the method includes providing or obtaining a sample, e.g., a sample as described herein, from a subject (e.g., a patient with NSCLC); determining the level of HSP90x in said sample; and administering an HSP90 20 inhibitor in combination with a taxane to the subject, if the HSP90X level is an intermediate or high circulating level of HSP90x. In certain embodiments, the HSP90 inhibitor and the taxane are administered in therapeutically effective amounts, e.g., an amount sufficient to reduce one or more symptoms associated with the cancer, e.g., lung cancer. 25 In certain embodiments, the subject treated by the methods can have, or is identified as having, an intermediate or high circulating level of HSP90x as described herein, and has (optionally) one or more of: a wild-type K-Ras gene; a history of smoking; NSCLC (e.g., relapsed and/or refractory NSCLC; or a particular stage of NSCLC, e.g., Stage IIIB or IV); a certain cancerous histology (e.g., adenocarcinoma 30 or squamous cell carcinoma); mutation in ALK gene; mutation in B-Raf gene; an alteration in copy number at the 14q31-33 gene locus; mutation in LKB 1 gene; a certain level of hypoxia; and/or disease progression during or after receiving at least one prior chemotherapeutic regimen (e.g., an NSCLC patient experiencing disease - 22 - 12041-7037WO / 1014 WO progression during or after receiving at least one prior platinum-containing chemotherapeutic regimen). In certain embodiments, the subject is previously selected or identified to be treated with a therapy comprising an HSP90 inhibitor in combination with a taxane, 5 e.g., previously evaluated as having an intermediate or high circulating level of HSP90x as described herein, and has (optionally) one or more of: a wild type K-Ras gene; a history of smoking; NSCLC (e.g., relapsed and/or refractory NSCLC; or a particular stage of NSCLC, e.g., Stage IIIB or IV); a certain cancerous histology (e.g., adenocarcinoma or squamous cell carcinoma); a p53 mutation; an alteration in copy 10 number at the 14q31-33 gene locus; and/or a certain level of hypoxia. In other embodiments, the subject is previously selected to be treated with a therapy comprising an HSP90 inhibitor by evaluating a sample obtained from the subject to detect the level of HSP90x and (optionally) the presence of one or more oncogenic alterations as described herein. 15 In some embodiments, the cancer being evaluated and/or treated is a NSCLC (e.g., relapsed and/or refractory NSCLC). In some embodiments, the NSCLC being evaluated and/or treated is adenocarcinoma or squamous cell carcinoma. In other embodiments, the cancer harbors a wild type K-Ras gene or gene product. In other embodiments, the cancer harbors a mutation in an ALK gene or gene product (e.g., 20 the NSCLC has an ALK rearrangement; the cancer expresses an EML4-ALK fusion; the cancer expresses a nucleophosmin-anaplastic lymphoma kinase fusion (NPM ALK fusion)); has a p53 mutation; and/or has an alteration in copy number at the 14q31-33 gene locus. In one embodiment, the cancer is resistant (e.g., partially or completely resistant) to an ALK inhibitor, but retains sensitivity to an HSP90 25 inhibitor alone or in combination with a taxane as described herein. In yet other embodiments, the cancer harbors a mutation in a p53 gene or gene product, and/or an EGFR gene or gene product. In yet other embodiments, the cancer has a mutation in an EGFR gene or gene product and has been pre-treated with a tyrosine kinase inhibitor. In one embodiment, the tumor or cancer is resistant (e.g., partially or 30 completely resistant) to a tyrosine kinase inhibitor (e.g., gefitinib), but retains sensitivity to an HSP90 inhibitor described herein. In yet other embodiments, the cancer has a wild type EGFR and/or K-Ras gene or gene product. In yet other embodiments, the cancer comprises squamous cells (e.g., squamous cell carcinoma). - 23 - 12041-7037WO / 1014 WO In yet other embodiments, the cancer is a large cell carcinoma or an adenocarcinoma of the lung. In yet another embodiment, the cancer is a particular subtype of NSCLC described herein elsewhere (e.g., adenocarcinoma or squamous cell carcinoma). In other embodiments, the cancer has at least 20%, 30%, 40%, 50%, 60%, 70% of the 5 cells showing a histology of squamous cell carcinoma. The methods can further include the step of monitoring the subject, e.g., for a change (e.g., an increase or decrease) in one or more of: the level of HSP90X; one or more of the biomarker(s) described herein; the rate of appearance of new lesions; the appearance of new disease-related symptoms; a change in quality of life; and/or any 10 other parameter related to clinical outcome. The subject can be monitored in one or more of the following periods: prior to beginning of treatment; during the treatment; or after the treatment has been administered. Monitoring can be used to evaluate the need for further treatment with the same HSP90 inhibitor or with another HSP90 inhibitor, alone or in combination, e.g., with a chemotherapeutic agent. 15 In one embodiment, the HSP90 inhibitor provided herein is a geldanamycin derivative, e.g., a benzoquinone or hydroquinone ansamycin HSP90 inhibitor (e.g., IPI-493 and/or IPI-504). In certain embodiments, the HSP90 inhibitor includes one or more benzoquinoidansamycins. For example, the HSP90 inhibitor can be chosen from one or more of IPI-493, 17-AG, IPI-504, 17-AAG (also known as 20 tanespimycinor CNF-1010), BIIB-021 (CNF-2024), BIIB-028, AUY-922 (also known as VER-49009), SNX-5422, ganetespib (also known as STA-9090), DS-2248, AT 13387, XL-888, MPC-3100, Debio 0932 (also known as CUDC-0305), alvespimycin (also known as 17-DMAG), CNF-1010, Macbecin (e.g., Macbecin I, Macbecin II), CCT-018159, CCT-129397, PU-H71, PF-04928473 (SNX-2112), or KW-2478. 25 In one embodiment, the Hsp90 inhibitor is a compound of formula 1:

R

4 OH X - O RW N R25 OH R 5 R6 R20

OR

1 R240 R2 R23 R7

R

1 0

R

2 2 Q 0

N-R

27 1 P 26 - 24 - 12041-7037WO / 1014 WO or the free base thereof; wherein independently for each occurrence: W is oxygen or sulfur; Q is oxygen, NR, N(acyl) or a bond; 5 X- is a conjugate base of a pharmaceutically acceptable acid; R for each occurrence is independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, heterocycloalkyl, aralkyl, heteroaryl, and heteroaralkyl;

R

1 is hydroxyl, alkoxyl, -OC(O)R 8 , -OC(O)OR 9 , -OC(O)NRioR 1 , -OS0 2

R

1 2 ,

-OC(O)NHSO

2

NR

1 3

R

1 4 , -NR 13

R

14 , or halide; and R 2 is hydrogen, alkyl, or aralkyl; or 10 R 1 and R 2 taken together, along with the carbon to which they are bonded, represent -(C=O)-, -(C=N-OR)-, -(C=N-NHR)-, or -(C=N-R)-;

R

3 and R 4 are each independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, aralkyl, heteroaryl, heteroaralkyl, and -[(CR2)p]-R 1 6 ;or R 3 taken together with R 4 represent a 15 4-8 membered optionally substituted heterocyclic ring;

R

5 is selected from the group consisting of H, alkyl, aralkyl, and a group having the formula la: 0

R

17 R17 R17

R

17 la 20 wherein R 17 is selected independently from the group consisting of hydrogen, halide, hydroxyl, alkoxyl, aryloxy, acyloxy, amino, alkylamino, arylamino, acylamino, aralkylamino, nitro, acylthio, carboxamide, carboxyl, nitrile, -COR 18 , -C0 2 Ri 8 , -N(Ri 8 )C0 2

R

1 9 , -OC(O)N(Ri 8

)(R

1 9 ), -N(Ri 8 )S0 2

R

1 9 , -N(Ris)C(O)N(Ris)(R 1 9 ), and -CH 2 0-heterocyclyl; 25 R 6 and R 7 are both hydrogen; or R 6 and R 7 taken together form a bond;

R

8 is hydrogen, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, aralkyl, heteroaryl, heteroaralkyl, or -[(CR2)p]-R 1 6 ;

R

9 is alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, aralkyl, heteroaryl, heteroaralkyl, or -[(CR2)p]-R 1 6 ; 30 RIO and R 1 are each independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, aralkyl, - 25 - 12041-7037WO / 1014 WO heteroaryl, heteroaralkyl, and -[(CR 2 )p]-RI 6 ; or RIO and R 11 taken together with the nitrogen to which they are bonded represent a 4-8 membered optionally substituted heterocyclic ring;

R

1 2 is alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, aralkyl, 5 heteroaryl, heteroaralkyl, or -[(CR2)p]-R16;

R

1 3 and R 1 4 are each independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, aralkyl, heteroaryl, heteroaralkyl, and -[(CR2)p]-R 16 ; or R 13 and R 14 taken together with the nitrogen to which they are bonded represent a 4-8 membered optionally substituted 10 heterocyclic ring;

R

1 6 for each occurrence is independently selected from the group consisting of hydrogen, hydroxyl, acylamino, -N(Ri 8

)COR

19 , -N(Ri 8

)C(O)OR

1 9 , -N(Ri 8 )S0 2

(R

19 ), -CON(Ri 8

)(R

19 ), -OC(O)N(Ri 8

)(R

19 ), -SO 2

N(RI

8

)(R

19 ), -N(Ri 8

)(R

19 ), -OC(O)ORi 8 ,

-COOR

18 , -C(O)N(OH)(Ri 8 ), -OS(O) 2 ORi 8 , -S(O) 2 ORi 8 , -OP(O)(ORi 8

)(OR

19 ), 15 -N(Ri 8 )P(O)(ORi 8

)(OR

1 9 ), and -P(O)(ORi 8

)(OR

1 9 ); p is 1, 2, 3, 4, 5, or 6;

R

18 for each occurrence is independently selected from the group consisting of hydrogen, alkyl, aryl, cycloalkyl, heterocycloalkyl, aralkyl, heteroaryl, and heteroaralkyl; 20 R 19 for each occurrence is independently selected from the group consisting of hydrogen, alkyl, aryl, cycloalkyl, heterocycloalkyl, aralkyl, heteroaryl, and heteroaralkyl; or R 18 taken together with R 19 represent a 4-8 membered optionally substituted ring;

R

20 , R 2 1 , R 2 2 , R 2 4 , and R 2 5 , for each occurrence are independently alkyl; 25 R 2 3 is alkyl, -CH 2 OH, -CHO, -COORi 8 , or -CH(ORi 8

)

2 ;

R

2 6 and R27 for each occurrence are independently selected from the group consisting of hydrogen, alkyl, aryl, cycloalkyl, heterocycloalkyl, aralkyl, heteroaryl, and heteroaralkyl; provided that when R 1 is hydroxyl, R 2 is hydrogen, R 6 and R 7 taken together 30 form a double bond, R 2 0 is methyl, R 2 1 is methyl, R 2 2 is methyl, R 2 3 is methyl, R 24 is methyl, R 2 5 is methyl, R 2 6 is hydrogen, R27 is hydrogen, Q is a bond, and W is oxygen; R 3 and R 4 are not both hydrogen nor when taken together represent an unsubstitutedazetidine; and - 26 - 12041-7037WO / 1014 WO the absolute stereochemistry at a stereogenic center of formula 1 can be R or S or a mixture thereof and the stereochemistry of a double bond can be E or Z or a mixture thereof. In other embodiments, the Hsp90 inhibitor is a compound of formula 3: H, ,H OH ) X N N MeMe N Me"" OH H I oOMe MeO Me HO 5

NH

2 3 or the free base thereof; wherein X- is the conjugate base of a pharmaceutically acceptable acid. In certain embodiments, the pharmaceutically acceptable acid has a pKa of between 10 about -10 and about 3. X- can be selected from the group consisting of chloride, bromide, iodide, H 2

PO

4 -, HS0 4 , methylsulfonate, benzenesulfonate, p toluenesulfonate, trifluoromethylsulfonate, 10-camphorsulfonate, naphthalene-1 sulfonic acid-5-sulfonate, ethan-1-sulfonic acid-2-sulfonate, cyclamate, thiocyanate, naphthalene-2-sulfonate, and oxalate. In one embodiment, X- is chloride. 15 In certain embodiments, the HSP90 inhibitor is 17-AG. In other embodiments, the HSP90 inhibitor is IPI-493. In other embodiments, the HSP90 inhibitor is IPI-504. In other embodiments, the HSP90 inhibitor is 17-AAG. In certain embodiments, one or more HSP90 inhibitors are administered as monotherapy or as a single agent, e.g., present in a composition, e.g., a 20 pharmaceutical composition including one HSP90 inhibitor. In other embodiments, the HSP90 inhibitor is administered in combination with a second therapeutic agent or a different therapeutic modality, e.g., anti-cancer agents, and/or in combination with surgical and/or radiation procedures. In other embodiments, the HSP90 inhibitor chosen from one or more of: 17 25 AAG (also known as tanespimycin or CNF-10 10), 17-AG, BIIB-021 (CNF-2024), BIIB-028, AUY-922 (also known as VER-49009), SNX-5422, ganetespib (also known as STA-9090), DS-2248, AT-13387, XL-888, MPC-3100, Debio 0932 (also - 27 - 12041-7037WO / 1014 WO known as CUDC-0305), alvespimycin (also known as 17-DMAG), CNF-1010, Macbecin (e.g., Macbecin I, Macbecin II), CCT-018159, CCT-129397, PU-H71, PF 04928473 (SNX-2112), or KW-2478. In yet other embodiments, two or more HSP90 inhibitors are administered in 5 combination, e.g., IPI-493 and/or IPI-504, in combination with one or more of: 17 AAG (also known as tanespimycin or CNF-10 10), 17-AG, BIIB-021 (CNF-2024), BIIB-028, AUY-922 (also known as VER-49009), SNX-5422, ganetespib (also known as STA-9090), DS-2248, AT-13387, XL-888, MPC-3100, Debio 0932 (also known as CUDC-0305), alvespimycin (also known as 17-DMAG), CNF-1010, 10 Macbecin (e.g., Macbecin I, Macbecin II), CCT-018159, CCT-129397, PU-H71, PF 04928473 (SNX-2112), or KW-2478. The HSP90 inhibitors described herein can be administered to the subject systemically (e.g., orally, parenterally, subcutaneously, intravenously, rectally, intramuscularly, intraperitoneally, intranasally, transdermally, or by inhalation or 15 intracavitary installation). Typically, the HSP90 inhibitors are administered subcutaneously, intravenously, or orally. In one embodiment, the second agent can be administered to the subject systemically (e.g., orally, parenterally, subcutaneously, intravenously, rectally, intramuscularly, intraperitoneally, intranasally, transdermally, or by inhalation or 20 intracavitary installation). In one embodiment, the second agent can be administered by the same or a different route of administration as the route of administration for the HSP90 inhibitor.In some embodiments, the second agent can be administered concurrently with the HSP90 inhibitor. In some embodiments, the second agent can be administered prior to the HSP90 inhibitor. In some embodiments, the second agent 25 can administered can be administered subsequent tothe HSP90 inhibitor. In one embodiment, the HSP90 inhibitor is IPI-504. IPI-504 can be administered intravenously weekly at a dose of about 300 to 500 mg/m 2 , typically about 350 to 500 mg/m 2 , and more typically about 450 mg/m 2 , alone or in combination with a second agent as described herein. 30 In some embodiments, the HSP90 inhibitor is a first-line treatment for the cancer or tumor, i.e., it is used in a subject who has not been previously administered another drug intended to treat the cancer. - 28 - 12041-7037WO / 1014 WO In other embodiments, the HSP90 inhibitor is a second-line treatment for the cancer, i.e., it is used in a subject who has been previously administered another drug intended to treat the cancer. In other embodiments, the HSP90 inhibitor is a third or fourth-line treatment 5 for the cancer, i.e., it is used in a subject who has been previously administered two or three other drugs intended to treat the cancer. In some embodiments, the HSP90 inhibitor is administered to a subject prior to, or following surgical excision/removal of the cancer. In some embodiments, the HSP90 inhibitor is administered to a subject before, 10 during, and/or after radiation treatment of the cancer. In some embodiments, the HSP90 inhibitor is administered to a subject, e.g., a cancer patient who is undergoing or has undergone cancer therapy (e.g., treatment with a chemotherapeutic, radiation therapy and/or surgery). In one embodiment, the second agent or the anti-cancer agent used in 15 combination with the HSP90 inhibitor is a cytotoxic or a cytostatic agent. In one embodiment, the second agent is a tubulin modulating agent (e.g., an agent that affects the function of microtubules, e.g., a taxane derivative or an epothilone derivative). In one embodiment, the second agent is a taxane, e.g. paclitaxel or taxol or a formulation thereof (e.g., nanoparticle albumin-bound paclitaxel (ABRAXANE@ 20 or nab-paclitaxel)), or docetaxel (e.g., as an injectable Docetaxel (Taxotere@)). For example, for treatment of a NSCLC, an HSP90 inhibitor can be administered in combination with a taxane, e.g., docetaxel (e.g., as a Docetaxel injection (Taxotere@)) or paclitaxel. In one embodiment, the taxane being administered is a taxane or taxoid analog or derivative known in the art, e.g., taxol, paclitaxel, docetaxel, or a derivative 25 thereof (e.g., US 4,814,470, US 5,587,489, US 5,719,177, US 5,721,268, US 5,728,725, US 5,763,477, US 5,824,701, US 5,912,263, US 5,912,264, US 5,955,489, US 5,994,576, US 5,998,656, US 6,005,138, US 6,011,056, US 6,017,935, US 6,018,073, US 6,025,385, US 6,028,205, US 6,051,724, US 6,136,808, US 6,147,234, US 6,162,920, US 6,191,290, US 6,201,140, US 6,268,381, US 6,335,362, US 30 6,339,164, US 6,358,996, US 6,362,217, US 6,369,244, US 6,462,208, US 6,482,963, US 6,521,660, US 6,541,508, US 6,552,205, US 6,596,880, US 6,649,777, US 6,649,778, US 6,750,246, US 6,794,523, US 6,872,842, US 6,869,973, US 6,906,101, US 7,019,150, US 7,153,884, US 7,157,474, US 7,160,919, US 7,220,872, US 7,230,013, US 7,279,586, US 7,317,113, US 7,589,111, US 7,598,290, US 7,667,054, - 29 - 12041-7037WO / 1014 WO US 7,745,650, US 8,138,361, US RE40,901, the contents of all of which are incorporated by reference herein). In some embodiments, the taxane is paclitaxel or a paclitaxel agent; or docetaxel or a docetaxel agent. In some embodiments, the taxane is paclitaxel or a 5 paclitaxel agent, e.g., TAXOL@, or protein-bound paclitaxel (e.g., ABRAXANE@). In one embodiment, a paclitaxel agent is a formulation of paclitaxel (e.g., TAXOL@) or a paclitaxel equivalent (e.g., for example, a prodrug of paclitaxel). Exemplary paclitaxel agents or equivalents include, but are not limited to, nanoparticle albumin bound paclitaxel (ABRAXANE@), docosahexaenoic acid bound-paclitaxel (DHA 10 paclitaxel, Taxoprexin), polyglutamate bound-paclitaxel (PG-paclitaxel, paclitaxel poliglumex, CT-2103, XYOTAX@), a tumor-activated prodrug (TAP) of paclitaxel, ANG105 (Angiopep-2 bound to three molecules of paclitaxel), paclitaxel-EC-1 (paclitaxel bound to the erbB2-recognizing peptide EC-1; see Li et al., Biopolymers (2007) 87:225-230), and glucose-conjugated paclitaxel (e.g., 2'-paclitaxel methyl 2 15 glucopyranosyl succinate, see Liu et al., Bioorganic & Medicinal ChemistryLetters (2007) 17:617-620). In certain embodiments, the paclitaxel agent is a paclitaxel equivalent. In certain embodiments, the paclitaxel equivalent is ABRAXANE@. In one embodiment, the HSP90 inhibitor is IPI-504. IPI-504 can be administered weekly at a dose of about 200 to 450 mg/m 2 , for example, about 200, 2 20 about 250, about 300, about 350, about 400, about 450, or about 500 mg/m , alone or in combination with a second agent provided herein. In one embodiment, the second agent is a taxane, e.g., docetaxel,docetaxel agent, paclitaxel, or paclitaxel agent (e.g., at a dose of about 40, about 50, about 60, about 70, or about 75 mg/m 2 ). In one embodiment, docetaxel (Taxotere") can be administered by intravenous (IV) infusion 25 every 3 weeks (Day 1 of each 21-day cycle), e.g., at a dose of 75 mg/m 2 over approximately 60 minutes. Kits In another aspect, provided herein are kits for evaluating a sample, e.g., a 30 sample from a lung cancer patient, to detect or determine the level of HSP90X. The kit includes a means for detection of (e.g., a reagent that specifically detects) HSP90X as described herein. In certain embodiments, the kit includes an HSP90 inhibitor. In another embodiment, the kit comprises an antibody, an antibody derivative, or an - 30 - 12041-7037WO / 1014 WO antibody fragment to a HSP90x or a biomarker polypeptide described herein. In one embodiment, the kit includes an antibody-based detection technique, such as immunofluorescence cell sorting (FACS), immunohistochemistry, antigen retrieval and/or microarray detection reagents. In one embodiment, at least one of the reagents 5 in the kit is an antibody that binds to HSP90x with a detectable label (e.g., a fluorescent, a radioactive, or an enzyme label). In certain embodiments, the kit is an ELISA or an immunohistochemistry (IHC) assay for detection of HSP90x. The kits described herein can additionally include instructions for use. In certain embodiments, instructions for appropriate combination or monotherapy with 10 an HSP90 inhibitor are disclosed. In certain embodiments, the instructions provide an end-user with information that a level of HSP90x in the sample (e.g., a serum or plasma sample) in the range of increased responsiveness as described herein indicates that the subject from whom the sample was obtained is likely to be responsive to a therapy comprising an HSP90 inhibitor. Or alternatively, the instructions provide an 15 end-user with information that a level of HSP90x in the sample (e.g., a serum or plasma sample) in the range of decreased responsiveness as described herein indicates that the subject from whom the sample was obtained is likely to show less response to a therapy comprising an HSP90 inhibitor, as compared to a subject having a higher level of HSP90x. 20 In other embodiments, the methods, assays, and/or kits described herein further include providing or generating, and/or transmitting information, e.g., a report, containing data of the evaluation or treatment determined by the methods, assays, and/or kits as described herein. The information can be transmitted to a report receiving party or entity (e.g., a patient, a health care provider, a diagnostic provider, 25 and/or a regulatory agency, e.g., the FDA), or otherwise submitting information about the methods, assays and kits disclosed herein to another party. The method can relate to compliance with a regulatory requirement, e.g., a pre- or post approval requirement of a regulatory agency, e.g., the FDA. In one embodiment, the report-receiving party or entity can determine if a predetermined requirement or reference value is met by 30 the data, and, optionally, a response from the report-receiving entity or party is received, e.g., by a physician, patient, diagnostic provider. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to - 31 - 12041-7037WO / 1014 WO which this disclosure belongs. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present disclosure, suitable methods and materials are described below. All publications, patent applications, patents, and other references mentioned herein are incorporated 5 by reference in their entirety. In addition, the materials, methods, and examples are illustrative only and not intended to be limiting. Other features and advantages of the present disclosure will be apparent from the detailed description, drawings, and from the claims. 10 BRIEF DESCRIPTION OF THE FIGURES Figure 1 is a bar graph showing the best percent change in target lesions from baseline in patients with non-small cell lung cancer treated with an HSP90 inhibitor, IPI-504, in combination with a taxane, docetaxel. Bars show the best percentage post treatment change in a patient's response from baseline; each bar represents a single 15 patient. Bars representing patients with low levels of HSP90x protein are shown with an asterisk, and bars representing patients with high levels of HSP90X are shown without an asterisk. Figure 2 is a graphic representation of the levels of HSP90X (ng/mL) in the 20 plasma of patients with non-small cell lung cancer compared to normal healthy donors prior to initiation of therapy. Figure 3 is a bar graph depicting the best percent change in target lesions from baseline in patients treated with IPI-504 and docetaxel. The bar graphs are numbered 25 1-18 and correspond to the following cancers: rectal cancer (1), NSCLC (2), NSCLC (3), NSCLC (4), unknown (5), NSCLC (6), testicular cancer (7), NSCLC (8), unknown (9), NSCLC (10), prostate cancer (11), NSCLC (12), salivary gland cancer (13), NSCLC (14), NSCLC (15), pancreatic cancer (16), melanoma (17), and pancreatic cell (18). High levels of HSP90x protein are indicated by a double 30 asterisk; mid levels of HSP90x protein are indicated by a single asterisk; low levels of HSP90x protein are indicated by no asterisk. HSP90x levels were evaluated prior to treatment. - 32 - 12041-7037WO / 1014 WO Figure 4 is a bar graph depicting the best percent change in target lesions from baseline in patients with non-small cell lung cancer treated with IPI-504 and docetaxel. High levels of HSP90x protein are indicated by a double asterisk; mid levels of HSP90x protein are indicated by a single asterisk; and low levels of HSP90x 5 protein are indicated by no asterisk. HSP90ax levels were evaluated prior to treatment. Figure 5 is a linear graph depicting the best percent change in target lesions from baseline in patients with non-small cell lung cancer treated with IPI-504 and docetaxel relative to HSP90x plasma levels (ng/mL). High levels of HSP90x protein 10 are indicated by a double asterisk; mid-levels of HSP90x protein are indicated by a single asterisk; low levels of HSP90x protein are indicated by no asterisk. A greater percent decrease in lesion size was detected in patients treated with IPI-504 and docetaxel having high plasma levels of HSP90x, followed by patients with mid plasma levels of HSP90x, and followed by patients with low HSP90x plasma levels. 15 Figures 6A-6B show comparison bar graphs of the best percent change in target lesions from baseline in patients with non-small cell lung cancer treated with IPI-504 alone (Figure 6A) or IPI-504 in combination with docetaxel (Figure 6B). Low levels of HSP90x protein are indicated by an asterisk; high levels of HSP90x 20 protein are indicated by no asterisk. Control subjects treated with placebo are labeled as "empty" (o). The patients in this study have either wild type or unknown K-Ras NSCLC status. Figures 6C-6D show comparison linear graphs of the best percent change in 25 target lesions from baseline in patients with non-small cell lung cancer treated with IPI-504 alone (Figure 6C) or IPI-504 in combination with docetaxel (Figure 6D) relative to the levels of HSP90x protein (ng/ml). Low levels of HSP90x protein are indicated by an asterisk; high levels of HSP90x protein are indicated by no asterisk. The patients in these figures have either wild type or unknown K-Ras NSCLC status. 30 Figure 7 is a linear graph showing the best percent change in target lesions from baseline in patients with non-small cell lung cancer treated with IPI-504 in combination with docetaxel in relation to the levels of HSP90x protein (ng/ml). - 33 - 12041-7037WO / 1014 WO Patients with mutant K-Ras are indicated by filled squares with an asterisk; patient with wild type/unknown K-Ras are indicated with filled squares without an asterisk. Low levels of HSP90x protein are indicated by filled squares; high levels of HSP90X protein are indicated by filled circles. 5 Figure 8 is a summary of the doses and dose scheduling for NSCLC patients evaluated in Example 3. Figure 9 is a bar graph showing the best percent change in target lesions from 10 baseline in NSCLC patients treated with IPI-504 in combination with docetaxel. Asterisk-labeled bars correspond to NSCLC patients carrying wild-type K-Ras, whereas the remaining shaded bars represent patients carrying a K-Ras mutation or subjects with an unknown mutation status. 15 Figure 10 is a bar graph showing the best percent change in target lesions from baseline in NSCLC patients with high or low levels of HSP90x-treated with IPI 504 in combination with docetaxel. The asterisk-labeled bar graphs correspond to NSCLC patients detected to have higher than median HSP90X level; unlabeled bar graphs correspond to NSCLC patient having lower than median HSP90X level. 20 Figure 11 is a bar graph showing the best percent change in target lesions from baseline in NSCLC patients with high or low levels of HSP90x-treated with IPI 504 in combination with docetaxel. The NSCLC patients were either K-Ras wild type or had an unknown KRAS status (not including patients having a mutant K-Ras). 25 Figure 12 is a bar graph showing the best percent change in target lesions from baseline in NSCLC patients (smokers vs. non-smokers) treated with IPI-504 in combination with docetaxel. 30 Figure 13 is a bar graph depicting a comparison of responsiveness to the combined IPI-504 and docetaxel treatment in lung cancer patients showing different cancer histologies: 1) adenocarcinoma, 2) bronchoalveolar, 3) large cell carcinoma, 4) - 34 - 12041-7037WO / 1014 WO squamous cell carcinoma, and 5) unspecified NSCLC. Patients were either K-Ras wild-type or have an unknown K-Ras status. Figure 14 is a bar graph depicting a comparison of responsiveness to the 5 combined IPI-504 and docetaxel treatment in NSCLC patients with a squamous cell histology. The unlabeled bar graphs correspond to NSCLC patients with a squamous cell histology detected to have higher than median HSP90ax level; the asterisk-labeled bar graph corresponds to NSCLC patient having lower than median HSP90aX level. 10 Figure 15 is a linear graph depicting the best percentage change from baseline as a function of the mean HSP90x concentration (ng/mL) in NSCLC patients treated with IPI-504 in combination with docetaxel. Data from all NSCLC patients (including patients carrying a K-Ras mutation) were included. 15 Figure 16 is a linear graph depicting the best percentage change from baseline as a function of the mean HSP90x concentration (ng/mL) in NSCLC patients treated with IPI-504 in combination with docetaxel. Data from NSCLC patients carrying either wild-type or unknown K-Ras status (excludes patients carrying a K-Ras mutation) were included. 20 Figure 17 provides a linear graph depicting the best percentage change from baseline as a function of the mean HSP90x concentration (ng/mL) in NSCLC patients treated with IPI-504 in combination with docetaxel. The values depicted are normalized with plasma protein values. A single asterisk-labeled square represents an 25 HSP90ax level lower than the median value; the unlabeled square represents an HSP90ax level higher than the median value. Figure 18 provides a linear graph depicting the best percentage change from baseline as a function of the mean HSP90x concentration (ng/mL) in NSCLC patients 30 treated with IPI-504 in combination with docetaxel. The values depicted are normalized with lab albumin values. A single asterisk-labeled square represents an HSP90ax level lower than the median value; the unlabeled square represents an HSP90ax level higher than the median value. - 35 - 12041-7037WO / 1014 WO Figure 19 is a linear graph depicting the best percentage change from baseline as a function of the mean HSP90x concentration (ng/mL) in NSCLC patients treated with IPI-504. 5 Figure 20 is a bar graph showing the best percent change in target lesions from baseline in NSCLC patients treated with IPI-504 with high or low levels of HSP90x. Asterisk-labeled bars correspond to NSCLC patients having higher than median levels of HSP90x, whereas unlabeled bars show lower than median levels of 10 HSP90x. Figure 21 is a graph showing the probability of survival of patients with non small cell lung cancer treated with IPI-504 in combination with docetaxel. X-axis indicates duration, in days, from follow-up treatment. Aggregate data for patients 15 with plasma HSP90ax levels greater than the median is indicated by the closed circles (# 1), and aggregate data for patients with plasma HSP90clevels less than or equal to the median is indicated by the open circles (# 2). Figure 22 is a graph showing the probability of survival of patients with non 20 small cell lung cancer treated with IPI-504 in combination with docetaxel. X-axis indicates duration, in days, from follow-up treatment. Figure 23 is a graph showing the probability of survival of patients with non small cell lung cancer treated with IPI-504 alone. 25 Figure 24 is a graph showing the best percent change in target lesion size from baseline in patients as a function of HSP90ax level and indicating that levels of HSP90x predict tumor responsiveness to combination treatment. The division between HSP90x high and HSP90x low groups was made based on a median cutoff; 30 subjects with low levels of HSP90x were those with values less than or equal to the median value (unlabeled) and subjects with high levels of HSP90x were those with values greater than the median value (designated as "o"). Bars labeled with asterisk indicate patients carrying a Ras mutation. - 36 - 12041-7037WO / 1014 WO Figure 25 is a graph showing the best percent change in target lesion size from baseline as a function of HSP90ax level and indicating that levels of HSP90X predict tumor responsiveness to combination treatment. The division between 5 HSP90x high and HSP90x low groups was made based on an optimized cutoff; subjects with low levels of HSP90x were those with values less than or equal to the optimized cutoff (unlabeled) and subjects with high levels of HSP90X were those with values greater than the optimized cutoff (designated as "o"). Bars labeled with asterisk indicate patients carrying a Ras mutation. 10 Figure 26 is a graph showing the probability of survival as a function of survival time in months in groups of subjects with high or low levels of HSP90X, as determined based on an optimized cutoff. 15 Figure 27 is a scatter plot of HSP90x tissue levels detected by IHC and HSP90x serum levels detected by ELISA (ng/ml) and shows an inverse correlation between tissue and serum levels, particularly in patients without known KRAS mutations. A patient carrying a K-Ras mutation is indicated by the arrow. No distinction is intended by the differences in shading of the boxes. 20 DETAILED DESCRIPTION Methods, assays and kits for identifying, assessing and/or treating a subject having cancer (e.g., a patient with lung cancer, e.g., NSCLC) are disclosed. In one embodiment, responsiveness of a subject to a treatment that includes an HSP90 25 inhibitor (e.g., a treatment that includes an HSP90 inhibitor in combination, e.g., in combination with another chemotherapeutic agents, such as a taxane, e.g., docetaxel or paclitaxel) is predicted by evaluating an alteration (e.g., an increased or decreased level) of HSP90x in a subject (e.g., a sample, e.g., a serum or plasma sample obtained from a lung cancer patient). 30 In one embodiment, responsiveness of a subject to an HSP90 inhibitor (in combination with a taxane) is predicted by evaluating the level of HSP90X in the subject (e.g., in a sample, e.g., a plasma or serum sample, obtained from a cancer patient (e.g., a patient with a lung cancer)), wherein an increased (or high) level of - 37 - 12041-7037WO / 1014 WO HSP90x in the sample relative to a predetermined value (e.g., a control sample) is indicative of increased responsiveness to an HSP90 inhibitor in combination with a taxane. In another embodiment, an increased (or high) level of circulating HSP90X relative to a predetermined value is indicative of longer patient survival, when the 5 patient is treated with an HSP90 inhibitor in combination with a taxane. Thus, the correlation between high levels of HSP90x expression and increased responsiveness to treatment with IPI-504 and docetaxel described herein indicates that analysis of plasma HSP90ax levels can be used to determine the responsiveness of a patient to combined treatment with docetaxel and IPI-504. Surprisingly, no clear 10 correlation to levels of HSP90x was observed in NSCLC patients undergoing an IPI 504 monotherapy. In one embodiment, the correlation between high levels of HSP90X and increased patient survival suggests that HSP90ax levels can be used to prognosticate patient outcomes in response to treatment of IPI-504 in combination with docetaxel. 15 Surprisingly, no clear correlation of levels of HSP90x to survival was observed in NSCLC patients undergoing an IPI-504 monotherapy. Accordingly, levels of circulating HSP90x can be used to evaluate responsiveness to, or monitor, a therapy that comprises an HSP90 inhibitor in combination with another chemotherapeutic agent, such as a taxane; to identify a 20 patient as likely to benefit from a therapy that comprises an HSP90 inhibitor; to stratify patient populations (e.g., to classify patients as being likely or unlikely to respond) to a therapy that comprises an HSP90 inhibitor; to predict a time course of disease or a probability of a significant event in the disease for such subjects (e.g., increased or decreased patient survival), and/or to more effectively monitor, treat or 25 prevent a cancer or tumor. Various aspects of the disclosure are described in further detail in the following subsections. Definitions 30 As used herein, each of the following terms has the meaning associated with it in this section. - 38 - 12041-7037WO / 1014 WO Chemical Definitions Definitions of specific functional groups and chemical terms are described in detail below. For purposes of this disclosure, the chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of 5 Chemistry and Physics, 75th Ed., inside cover, and specific functional groups are generally defined as described therein. Additionally, general principles of organic chemistry, as well as specific functional moieties and reactivity, are described in, for example, Organic Chemistry, Thomas Sorrell, University Science Books, Sausalito, 1999; Smith and March March's Advanced Organic Chemistry, 5 Edition, John 10 Wiley & Sons, Inc., New York, 2001; Larock, Comprehensive Organic Transformations, VCH Publishers, Inc., New York, 1989; and Carruthers, Some Modern Methods of Organic Synthesis, 3 rd Edition, Cambridge University Press, Cambridge, 1987. Certain compounds of the present disclosure can comprise one or more 15 asymmetric centers, and thus can exist in various isomeric forms, i.e., stereoisomers (enantiomers, diastereomers, cis-trans isomers, E/Z isomers, etc.). Thus, inventive compounds and pharmaceutical compositions thereof can be in the form of an individual enantiomer, diastereomer or other geometric isomer, or can be in the form of a mixture of stereoisomers. Enantiomers, diastereomers and other geometric 20 isomers can be isolated from mixtures (including racemic mixtures) by any method known to those skilled in the art, including chiral high pressure liquid chromatography (HPLC) and the formation and crystallization of chiral salts or prepared by asymmetric syntheses; see, for example, Jacques, et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen, S.H., et al., 25 Tetrahedron 33:2725 (1977); Eliel, E.L. Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); Wilen, S.H. Tables of Resolving Agents and Optical Resolutions p. 268 (E.L. Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, IN 1972). Carbon atoms, unless otherwise specified, can optionally be substituted with 30 one or more substituents. The number of substituents is typically limited by the number of available valences on the carbon atom, and can be substituted by replacement of one or more of the hydrogen atoms that would be available on the unsubstituted group. Suitable substituents are known in the art and include, but are not limited to, alkyl, alkenyl, alkynyl, alkoxy, alkoxy, aryl, aryloxy, arylthio, aralkyl, - 39 - 12041-7037WO / 1014 WO heteroaryl, heteroaralkyl, cycloalkyl, heterocyclyl, halo, azido, hydroxyl, thio, alkthiooxy, amino, nitro, nitrile, imino, amido, carboxylic acid, aldehyde, carbonyl, ester, silyl, alkylthio, haloalkyl (e.g., perfluoroalkyl such as -CF 3 ), =0, =S, and the like. 5 When a range of values is listed, it is intended to encompass each value and sub-range within the range. For example, an alkyl group containing 1-6 carbon atoms

(C

1

-

6 alkyl) is intended to encompass, C 1 , C 2 , C 3 , C 4 , C 5 , C 6 , C 1

-

6 , C 2

-

6 , C 3

-

6 , C 4

-

6 , C 5 6, C 1

-

5 , C 2

-

5 , C3- 5 , C 4

-

5 , C 1 -4, C2-4, C3-4, C1 3 , C 2 3 , and C 1

-

2 alkyl. The term "alkyl," as used herein, refers to saturated, straight- or branched 10 chain hydrocarbon radical containing between one and thirty carbon atoms. In certain embodiments, the alkyl group contains 1-20 carbon atoms. Alkyl groups, unless otherwise specified, can optionally be substituted with one or more substituents. In certain embodiments, the alkyl group contains 1-10 carbon atoms. In certain embodiments, the alkyl group contains 1-6 carbon atoms. In certain embodiments, 15 the alkyl group contains 1-5 carbon atoms. In certain embodiments, the alkyl group contains 1-4 carbon atoms. In certain embodiments, the alkyl group contains 1-3 carbon atoms. In certain embodiments, the alkyl group contains 1-2 carbon atoms. In certain embodiments, the alkyl group contains 1 carbon atom. Examples of alkyl radicals include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, 20 iso-butyl, sec-butyl, sec-pentyl, iso-pentyl, tert-butyl, n-pentyl, neopentyl, n-hexyl, sec-hexyl, n-heptyl, n-octyl, n-decyl, n-undecyl, dodecyl, and the like. The term "alkenyl," as used herein, denotes a straight- or branched-chain hydrocarbon radical having at least one carbon-carbon double bond by the removal of a single hydrogen atom, and containing between two and thirty carbon atoms. 25 Alkenyl groups, unless otherwise specified, can optionally be substituted with one or more substituents. In certain embodiments, the alkenyl group contains 2-20 carbon atoms. In certain embodiments, the alkenyl group contains 2-10 carbon atoms. In certain embodiments, the alkenyl group contains 2-6 carbon atoms. In certain embodiments, the alkenyl group contains 2-5 carbon atoms. In certain embodiments, 30 the alkenyl group contains 2-4 carbon atoms. In certain embodiment, the alkenyl group contains 2-3 carbon atoms. In certain embodiments, the alkenyl group contains 2 carbon atoms. Alkenyl groups include, for example, ethenyl, propenyl, butenyl, 1 methyl-2-buten-1-yl, and the like. - 40 - 12041-7037WO / 1014 WO The term "alkynyl," as used herein, denotes a straight- or branched-chain hydrocarbon radical having at least one carbon-carbon triple bond by the removal of a single hydrogen atom, and containing between two and thirty carbon atoms. Alkynyl groups, unless otherwise specified, can optionally be substituted with one or more 5 substituents. In certain embodiments, the alkynyl group contains 2-20 carbon atoms. In certain embodiments, the alkynyl group contains 2-10 carbon atoms. In certain embodiments, the alkynyl group contains 2-6 carbon atoms. In certain embodiments, the alkynyl group contains 2-5 carbon atoms. In certain embodiments, the alkynyl group contains 2-4 carbon atoms. In certain embodiments, the alkynyl group contains 10 2-3 carbon atoms. In certain embodiments, the alkynyl group contains 2 carbon atoms. Representative alkynyl groups include, but are not limited to, ethynyl, 2 propynyl (propargyl), 1-propynyl, and the like. The terms "cycloalkyl," used alone or as part of a larger moiety, refer to a saturated monocyclic or bicyclic hydrocarbon ring system having from 3-15 carbon 15 ring members. Cycloalkyl groups, unless otherwise specified, can optionally be substituted with one or more substituents. In certain embodiments, cycloalkyl groups contain 3-10 carbon ring members. In certain embodiments, cycloalkyl groups contain 3-9 carbon ring members. In certain embodiments, cycloalkyl groups contain 3-8 carbon ring members. In certain embodiments, cycloalkyl groups contain 3-7 20 carbon ring members. In certain embodiments, cycloalkyl groups contain 3-6 carbon ring members. In certain embodiments, cycloalkyl groups contain 3-5 carbon ring members. Cycloalkyl groups include, without limitation, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. The term "cycloalkyl" also includes saturated hydrocarbon ring systems that are fused to one or more aryl or 25 heteroaryl rings, such as decahydronaphthyl or tetrahydronaphthyl, where the point of attachment is on the saturated hydrocarbon ring. The term "aryl" used alone or as part of a larger moiety (as in "aralkyl"), refers to an aromatic monocyclic and bicyclic hydrocarbon ring system having a total of 6-10 carbon ring members. Aryl groups, unless otherwise specified, can optionally 30 be substituted with one or more substituents. In certain embodiments of the present disclosure, "aryl" refers to an aromatic ring system which includes, but not limited to, phenyl, biphenyl, naphthyl, anthrancyl and the like, which can bear one or more substituents. Also included within the scope of the term "aryl," as it is used herein, is a group in which an aryl ring is fused to one or more non-aromatic rings, such as - 41 - 12041-7037WO / 1014 WO indanyl, phthalimidyl or tetrahydronaphthalyl, and the like, where the point of attachment is on the aryl ring. The term "aralkyl" refers to an alkyl group, as defined herein, substituted by aryl group, as defined herein, wherein the point of attachment is on the alkyl group. 5 The term "heteroatom" refers to boron, phosphorus, selenium, nitrogen, oxygen, or sulfur, and includes any oxidized form of nitrogen or sulfur, and any quaternized form of abasic nitrogen. The terms "heteroaryl" used alone or as part of a larger moiety, e.g., "heteroaralkyl," refer to an aromatic monocyclic or bicyclic hydrocarbon ring system 10 having 5-10 ring atoms wherein the ring atoms comprise, in addition to carbon atoms, from one to five heteroatoms. Heteroaryl groups, unless otherwise specified, can optionally be substituted with one or more substituents. When used in reference to a ring atom of a heteroaryl group, the term "nitrogen" includes a substituted nitrogen. Heteroaryl groups include, without limitation, thienyl, furanyl, pyrrolyl, imidazolyl, 15 pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl, naphthyridinyl, and pteridinyl. The terms "heteroaryl" and "heteroar-," as used herein, also include groups in which a heteroaryl ring is fused to one or more aryl, cycloalkyl or heterocycloalkyl rings, wherein the point of attachment is on the 20 heteroaryl ring. Nonlimiting examples include indolyl, isoindolyl, benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzthiazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H-quinolizinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl, and tetrahydroisoquinolinyl. 25 The term "heteroaralkyl" refers to an alkyl group, as defined herein, substituted by a heteroaryl group, as defined herein, wherein the point of attachment is on the alkyl group. As used herein, the terms "heterocycloalkyl" or "heterocyclyl" refer to a stable non-aromatic 5-7 membered monocyclic hydrocarbon or stable non-aromatic 7-10 30 membered bicyclic hydrocarbon that is either saturated or partially unsaturated, and having, in addition to carbon atoms, one or more heteroatoms. Heterocycloalkyl or heterocyclyl groups, unless otherwise specified, can optionally be substituted with one or more substituents. When used in reference to a ring atom of a heterocycloalkyl group, the term "nitrogen" includes a substituted nitrogen. The point of attachment of - 42 - 12041-7037WO / 1014 WO a heterocycloalkyl group can be at any of its heteroatom or carbon ring atoms that results in a stable structure. Examples of heterocycloalkyl groups include, without limitation, tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl, pyrrolidonyl, piperidinyl, pyrrolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, 5 decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, diazepinyl, oxazepinyl, thiazepinyl, morpholinyl, and quinuclidinyl. "Heterocycloalkyl" also include groups in which the heterocycloalkyl ring is fused to one or more aryl, heteroaryl or cycloalkyl rings, such as indolinyl, chromanyl, phenanthridinyl, or tetrahydroquinolinyl, where the radical or point of attachment is on the 10 heterocycloalkyl ring. The term "unsaturated," as used herein, means that a moiety has one or more double or triple bonds. As used herein, the term "partially unsaturated" refers to a ring moiety that includes at least one double or triple bond. The term "partially unsaturated" is 15 intended to encompass rings having multiple sites of unsaturation, but is not intended to include aromatic groups, such as aryl or heteroaryl moieties, as defined herein. The term "diradical" as used herein refers to an alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, aralkyl, heteroaryl, and heteroaralkyl groups, as described herein, wherein 2 hydrogen atoms are removed to form a divalent moiety. 20 Diradicals are typically end with a suffix of "-ene". For example, alkyl diradicals are referred to as alkylenes (for example: , and -(CR' 2 )x wherein R' is hydrogen or other substituent and x is 1, 2, 3, 4, 5 or 6); alkenyl diradicals are referred to as "alkenylenes"; alkynyl diradicals are referred to as "alkynylenes"; aryl and aralkyl diradicals are referred to as "arylenes" and 25 "aralkylenes," respectively (for example: - ); heteroaryl and heteroaralkyl diradicals are referred to as "heteroarylenes" and "heteroaralkylenes," 10 respectively (for example: ); cycloalkyldiradicals are referred to as "cycloalkylenes"; heterocycloalkyl diradicals are referred to as "heterocycloalkylenes"; and the like. - 43 - 12041-7037WO / 1014 WO The terms "halo," "halogen" and "halide" as used herein refer to an atom selected from fluorine (fluoro, F), chlorine (chloro, Cl), bromine (bromo, Br), and iodine (iodo, I). As used herein, the term "haloalkyl" refers to an alkyl group, as described 5 herein, wherein one or more of the hydrogen atoms of the alkyl group is replaced with one or more halogen atoms. In certain embodiments, the haloalkyl group is a perhaloalkyl group, that is, having all of the hydrogen atoms of the alkyl group replaced with halogens (e.g., such as the perfluoroalkyl group -CF 3 ). As used herein, the term "azido" refers to the group -N 3 . 10 As used herein, the term "nitrile" refers to the group -CN. As used herein, the term "nitro" refers to the group -NO 2 . As used herein, the term "hydroxyl" or "hydroxy" refers to the group -OH. As used herein, the term "thiol" or "thio" refers to the group -SH. As used herein, the term "carboxylic acid" refers to the group -CO 2 H. 15 As used herein, the term "aldehyde" refers to the group -CHO. As used herein, the term "alkoxy" refers to the group -OR', wherein R' is an alkyl, alkenyl or alkynyl group, as defined herein. As used herein, the term "aryloxy" refers to the group -OR', wherein each R' is an aryl or heteroaryl group, as defined herein. 20 As used herein, the term "alkthiooxy" refers to the group -SR', wherein each R' is, independently, a carbon moiety, such as, for example, an alkyl, alkenyl, or alkynyl group, as defined herein. As used herein, the term "arylthio" refers to the group -SR', wherein each R' is an aryl or heteroaryl group, as defined herein. 25 As used herein, the term "amino" refers to the group -NR' 2 , wherein each R' is, independently, hydrogen, a carbon moiety, such as, for example, an alkyl, alkenyl, alkynyl, aryl or heteroaryl group, as defined herein, or two R' groups together with the nitrogen atom to which they are bound form a 5-8 membered ring. As used herein, the term "carbonyl" refers to the group -C(=O)R', wherein R' 30 is, independently, a carbon moiety, such as, for example, an alkyl, alkenyl, alkynyl, aryl or heteroaryl group, as defined herein. As used herein, the term "ester" refers to the group -C(=O)OR' or OC(=O)R' wherein each R' is, independently, a carbon moiety, such as, for example, an alkyl, alkenyl, alkynyl, aryl or heteroaryl group, as defined herein. - 44 - 12041-7037WO / 1014 WO As used herein, the term "amide" or "amido" refers to the group C(=0)N(R')2 or - NR'C(=O)R' wherein each R' is, independently, hydrogen or a carbon moiety, such as, for example, an alkyl, alkenyl, alkynyl, aryl or heteroaryl group, as defined herein, or two R' groups together with the nitrogen atom to which 5 they are bound form a 5-8 membered ring. The term "sulfonamido" or "sulfonamide" refers to the group -N(R')SO 2 R' or

-SO

2

N(R')

2 , wherein each R' is, independently, hydrogen or a carbon moiety, such as, for example, an alkyl, alkenyl, alkynyl, aryl or heteroaryl group, as defined herein, or two R' groups together with the nitrogen atom to which they are bound form a 5-8 10 membered ring. The term "sulfamido" or "sulfamide" refers to the group -NR'SO 2

N(R')

2 , wherein each R' is, independently, hydrogen or a carbon moiety, such as, for example, an alkyl, alkenyl, alkynyl, aryl or heteroaryl group, as defined herein, or two R' groups together with the nitrogen atom to which they are bound form a 5-8 15 membered ring. As used herein, the term "imide" or "imido" refers to the group C(=NR')N(R') 2 or -NR'C(=NR')R' wherein each R' is, independently, hydrogen or a carbon moiety, such as, for example, an alkyl, alkenyl, alkynyl, aryl or heteroaryl group, as defined herein, or wherein two R' groups together with the nitrogen atom to 20 which they are bound form a 5-8 membered ring. As used herein "silyl" refers to the group -SiR' wherein R' is a carbon moiety, such as, for example, an alkyl, alkenyl, alkynyl, aryl or heteroaryl group. In some cases, the HSP90 inhibitor can contain one or more basic functional groups (e.g., such as an amino group), and thus is capable of forming 25 pharmaceutically acceptable salts with pharmaceutically acceptable acids. The term "pharmaceutically acceptable salts" in these instances refers to the relatively non toxic, inorganic and organic acid addition salts. These salts can be prepared in situ in the administration vehicle or the dosage form manufacturing process, or by separately treating the compound in its free base form with a suitable acid. Examples of 30 pharmaceutically acceptable, nontoxic acid addition salts from inorganic acids include, but are not limited to, hydrochloric, hydrobromic, phosphoric, sulfuric, nitric and perchloric acid or from organic acids include, but are not limited to, acetic, adipic, alginic, ascorbic, aspartic, 2-acetoxybenzoic, benzenesulfonic, benzoic, bisulfonic, boric, butyric, camphoric, camphorsulfonic, citric, cyclopentanepropionic, digluconic, - 45 - 12041-7037WO / 1014 WO dodecylsulfonic, ethanesulfonic, 1,2-ethanedisulfonic, formic, fumaric, glucoheptonic, glycerophosphonic, gluconic, hemisulfonic, heptanoic, hexanoic, hydroiodic, 2 hydroxyethanesulfonic, hydroxymaleic, isothionic, lactobionic, lactic, lauric, lauryl sulfonic, malic, maleic, malonic, methanesulfonic, 2-naphthalenesulfonic, napthylic, 5 nicotinic, oleic, oxalic, palmitic, pamoic, pectinic, persulfonic, 3-phenylpropionic, picric, pivalic, propionic, phenylacetic, stearic, succinic, salicyclic, sulfanilic, tartaric, thiocyanic, p-toluenesulfonic, undecanoic, and valeric acid addition salts, and the like. In other cases, the HSP90 inhibitor can contain one or more acidic functional groups, and thus is capable of forming pharmaceutically acceptable salts with 10 pharmaceutically acceptable bases. The term "pharmaceutically acceptable salts" in these instances refers to the relatively non-toxic, inorganic and organic base addition salts. These salts can likewise be prepared in situ in the administration vehicle or the dosage form manufacturing process, or by separately treating the compound in its free acid form with a suitable base. Examples of suitable bases include, but are not limited 15 to, metal hydroxides, metal carbonates or metal bicarbonates, wherein the metal is an alkali or alkaline earth metal such as lithium, sodium, potassium, calcium, magnesium, or aluminum. Suitable bases can also include ammonia or organic primary, secondary or tertiary amines. Representative organic amines useful for the formation of base addition salts include, for example, ethylamine, diethylamine, 20 ethylenediamine, ethanolamine, diethanolamine, piperazine and the like (see, e.g., Berge et al., supra). The term "solvate" refers to a compound of the present disclosure having either a stoichiometric or non-stoichiometric amount of a solvent associated with the compound. The solvent can be water (i.e., a hydrate), and each molecule of inhibitor 25 can be associated with one or more molecules of water (e.g., monohydrate, dihydrate, trihydrate, etc.). The solvent can also be an alcohol (e.g., methanol, ethanol, propanol, isopropanol, etc.), a glycol (e.g., propylene glycol), an ether (e.g., diethyl ether), an ester (e.g., ethyl acetate), or any other suitable solvent. The HSP90 inhibitor can also exist as a mixed solvate (i.e., associated with two or more different 30 solvents). The term "sugar" as used herein refers to a natural or an unnatural monosaccharide, disaccharide or oligosaccharide comprising one or more pyranose or furanose rings. The sugar can be covalently bonded to the steroidal alkaloid of the present disclosure through an ether linkage or through an alkyl linkage. In certain - 46 - 12041-7037WO / 1014 WO embodiments the saccharide moiety can be covalently bonded to a steroidal alkaloid of the present disclosure at an anomeric center of a saccharide ring. Sugars can include, but are not limited to ribose, arabinose, xylose, lyxose, allose, altrose, glucose, mannose, gulose, idose, galactose, talose, glucose, and trehalose. 5 Non-Chemical Definitions As used herein, each of the following terms has the meaning associated with it in this section. As used herein, the articles "a" and "an" refer to one or to more than one (e.g., to at 10 least one) of the grammatical object of the article. The term "or" is used herein to mean, and is used interchangeably with, the term "and/or," unless context clearly indicates otherwise. "About" and "approximately" shall generally mean an acceptable degree of error for the quantity measured given the nature or precision of the measurements. Exemplary degrees 15 of error are within 20 percent (%), typically, within 10%, and more typically, within 5% of a given value or range of values. The term "altered level" of a biomarker, e.g., HSP90x, as described herein refers to an increase or decrease in the level of a marker in a subject or a sample, such as a sample derived from a patient suffering from cancer or a similar disorder (e.g., 20 lung cancer, e.g., NSCLC or SCLC), that is greater or less than, e.g., the standard error of the assay employed to assess the amount. In embodiments, the alteration can be at least twice, at least twice three, at least twice four, at least twice five, or at least twice ten or more times greater than or less than the level of the biomarkers in a control sample (e.g., a sample from a healthy subject not having the associated 25 disease), or the median level in several control samples. An "altered level"can be determined at the protein or nucleic acid (e.g., mRNA) level. The term "circulating level" of a biomarker, e.g., HSP90X, refers to a level of the biomarker present in circulation in a subject, for example, the level of the biomarker that is not found in a tissue or site (e.g., a tumor tissue or site). A 30 circulating level of a biomarker can include a level of a biomarker found in, for example, plasma, serum, blood, saliva and other bodily fluids. In one embodiment, the circulating level of the biomarker is not inside a cell or tissue. - 47 - 12041-7037WO / 1014 WO "Binding compound" shall refer to a binding composition, such as a small molecule, an antibody, a peptide, a peptide or non-peptide ligand, a protein, an oligonucleotide, an oligonucleotide analog, such as a peptide nucleic acid, a lectin, or any other molecular entity that is capable of specifically binding to a target protein or 5 molecule or stable complex formation with an analyte of interest, such as a complex of proteins. "Binding moiety" means any molecule to which molecular tags can be directly or indirectly attached that is capable of specifically binding to an analyte. Binding moieties include, but are not limited to, antibodies, antibody binding compositions, 10 peptides, proteins, nucleic acids and organic molecules having a molecular weight of up to about 1000 daltons and containing atoms selected from the group consisting of hydrogen, carbon, oxygen, nitrogen, sulfur and phosphorus. A "biomarker" or "marker" is a gene, mRNA, or polypeptide or protein that undergoes alterations in the level, e.g., expression that are associated with cancer or 15 responsiveness to treatment with an HSP90 inhibitor alone or in combination with a taxane. The alteration can be in amount and/or activity in a sample (e.g., a blood, plasma, or a serum sample) obtained from a subject having cancer, as compared to its amount and/or activity, in a biological sample obtained from a reference value, e.g., a healthy subject (e.g., a control); such alterations in expression and/or activity are 20 associated with a disease state, such as cancer. For example, a marker which is associated with lung cancer (e.g., NSCLC) or predictive of responsiveness to HSP90 inhibitors can have an altered expression level, protein level, or protein activity, in a sample obtained from a subject having, or suspected of having, lung cancer as compared to a biological sample obtained from a control subject (e.g., a healthy 25 individual). In one embodiment, the biomarker is a predictive biomarker, and thus distinguishes a patient who can benefit from a patient who will not benefit by treatment with a particular drug. In other embodiments, the biomarker is a prognostic biomarker, and thus indicates disease aggressiveness in a patient. The terms "cancer" or "tumor" refer to the presence of cells possessing 30 characteristics typical of cancer-causing cells, such as uncontrolled proliferation, immortality, metastatic potential, rapid growth and proliferation rate, and certain characteristic morphological features. Cancer cells are often in the form of a tumor, but such cells can exist alone within an animal, or can be a non-tumorigenic cancer cell, such as a leukemia cell. As used herein, the term "cancer" includes premalignant - 48 - 12041-7037WO / 1014 WO as well as malignant cancers. In certain embodiments, the cancer is chosen from lung cancer, pancreatic cancer, or melanoma. In other embodiment, the lung cancer is chosen from one or more of the following: non-small cell lung cancer (NSCLC), small cell lung cancer (SCLC), squamous cell carcinoma of the lung, adenocarcinoma 5 of the lung, and/or bronchogenic carcinoma. In one embodiment, the lung cancer is non-small cell lung cancer (NSCLC), e.g., relapsed and/or refractory NSCLC; or adenocarcinoma and/or squamous cell carcinoma. "Chemotherapeutic agent" means a chemical substance, such as a cytotoxic or cytostatic agent, that is used to treat a condition, particularly cancer. 10 As used herein, "cancer" and "tumor" are synonymous terms. As used herein, "cancer therapy" and "cancer treatment" are synonymous terms. As used herein, "chemotherapy" and "chemotherapeutic" and "chemotherapeutic agent" are synonymous terms. 15 Cancer is "inhibited" if at least one symptom of the cancer is alleviated, terminated, slowed, or prevented. As used herein, cancer is also "inhibited" if recurrence or metastasis of the cancer is reduced, slowed, delayed, or prevented. A "nucleic acid" "marker" or "biomarker" is a nucleic acid (e.g., DNA, mRNA, cDNA) encoded by or corresponding to a marker as described herein. For 20 example, such marker nucleic acid molecules include DNA (e.g., genomic DNA and cDNA) comprising the entire or a partial sequence of any of the biomarkers set forth herein, or the complement or hybridizing fragment of such a sequence. A "marker protein" is a protein encoded by or corresponding to a marker provided herein. A marker protein comprises the entire or a partial sequence of a protein encoded by any 25 of the biomarkers set forth herein, or a fragment thereof. The terms "protein" and "polypeptide" are used interchangeably herein. A marker is "fixed" to a substrate if it is covalently or non-covalently associated with the substrate such that the substrate can be rinsed with a fluid (e.g., standard saline citrate, pH 7.4) without a substantial fraction of the marker 30 dissociating from the substrate. The terms "homology" or "identity," as used interchangeably herein, refer to sequence similarity between two polynucleotide sequences or between two polypeptide sequences, with identity being a more strict comparison. The phrases "percent identity or homology" and "% identity or homology" refer to the percentage - 49 - 12041-7037WO / 1014 WO of sequence similarity found in a comparison of two or more polynucleotide sequences or two or more polypeptide sequences. "Sequence similarity" refers to the percent similarity in base pair sequence (as determined by any suitable method) between two or more polynucleotide sequences. Two or more sequences can be 5 anywhere from 0-100% similar, or any integer value there between. Identity or similarity can be determined by comparing a position in each sequence that can be aligned for purposes of comparison. When a position in the compared sequence is occupied by the same nucleotide base or amino acid, then the molecules are identical at that position. A degree of similarity or identity between polynucleotide sequences 10 is a function of the number of identical or matching nucleotides at positions shared by the polynucleotide sequences. A degree of identity of polypeptide sequences is a function of the number of identical amino acids at positions shared by the polypeptide sequences. A degree of homology or similarity of polypeptide sequences is a function of the number of amino acids at positions shared by the polypeptide sequences. The 15 term "substantial homology," as used herein, refers to homology of at least 50%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or more. "Heat shock protein (Hsp) 90" or "HSP90," as used herein, includes each member of the family of heat shock proteins having a mass of about 90-kilo Daltons. 20 For example, in humans the highly conserved Hsp90 family includes cytosolic Hsp90a and Hsp90P isoforms, as well as GRP94, which is found in the endoplasmic reticulum, and HSP75/TRAP1, which is found in the mitochondrial matrix. Hsp90 plays an integral role in protein homeostasis and regulates the stability of key proteins involved in oncogenesis, cancer cell proliferation, and survival through its role as a 25 protein chaperone (Kanelakis K. C. et al. (2003) Methods Enzymol. 364:159-173; Hanahan D. et al. (2000) Cell. 100(1):57-70). Hsp90 can preferentially chaperone mutant oncoproteins over wild-type versions, further increasing its attractiveness as a therapeutic target (Nathan D. F. et al. (1995) Mol Cell Biol. 15(7):3917-3925; Rutherford S. L. et al. (1998) Nature 396(6709):336-342; Grbovic 0. M. et al. (2006) 30 Proc Natl Acad Sci U S A. 103(1):57-62; Shimamura T. et al. (2005) Cancer Res.65(14):6401-6408). Exemplary amino acid and nucleotide sequences for human HSP90x are disclosed herein as SEQ ID NO:1, 3 and 2, 4, respectively. - 50 - 12041-7037WO / 1014 WO "HSP90 inhibiting agent" or "HSP90 inhibitor," as used herein, refers to a compound that can inhibit the biological activity of HSP90. Biological activities can also include patient response as set forth in this application. Exemplary HSP90 inhibiting agents include, but are not limited to, IPI-493 (Infinity Pharm.), 17-AG, 5 IPI-504 (Infinity Pharm.), 17-AAG (also known as tanespimycin or CNF-1010; BMS), BIIB-021 (also known as CNF-2024, Biogen IDEC), BIIB-028 (Biogen IDEC), AUY-922 (also known as VER-49009, Novartis), SNX-5422 (Pfizer), STA 9090, AT-13387 (Astex), XL-888 (Exelixis), MPC-3100 (Myriad), CU-0305 (Curis), 17-DMAG, CNF-1010, a Macbecin (e.g., Macbecin I, Macbecin II), CCT-018159, 10 CCT-129397, PU-H71 (Memorial Sloan Kettering Cancer Center), PF-04928473 (SNX-2112), and TAE684. Other HSP90 inhibitors are disclosed in Zhang, M-Q. et al., J. Med. Chem. 51(18):5494-5497 (2008) and Menzella, H. et al., J. Med. Chem., 52(6):15128-1521 (2009). An "overexpression" or "significantly higher level of expression" of the gene 15 products refers to an expression level or copy number in a test sample that is greater than the standard error of the assay employed to assess the level of expression. In embodiments, the overexpression can be at least two, at least three, at least four, at least five, or at least ten or more times the expression level of the gene products in a control sample (e.g., a sample from a healthy subject not afflicted with cancer), or the 20 average expression level of gene products in several control samples. The term "probe" refers to any molecule which is capable of selectively binding to a specifically intended target molecule, for example a marker provided herein. Probes can be either synthesized by one skilled in the art, or derived from appropriate biological preparations. For purposes of detection of the target molecule, 25 probes can be specifically designed to be labeled, as described herein. Examples of molecules that can be utilized as probes include, but are not limited to, RNA, DNA, proteins, antibodies, and organic monomers. "Responsiveness," to "respond" to treatment, and other forms of this verb, as used herein, refer to the reaction of a subject to treatment with an HSP90 inhibitor, 30 alone or in combination, e.g., in combination with a taxane. As an example, a subject responds to treatment with an HSP90 inhibiting agent if growth or size of a tumor in the subject is retarded or reduced about 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or more. In another example, a subject responds to treatment with an HSP90 inhibitor, alone or in combination, if a tumor in the subject shrinks by about - 51 - 12041-7037WO / 1014 WO 5%, 10%, 20%, 30%, 40%, 50% or more as determined by any appropriate measure, e.g., by mass or volume. In another example, a subject responds to treatment with an HSP90 inhibitor, alone or in combination, if the subject experiences a life expectancy extended by about 5%, 10%, 20%, 30%, 40%, 50% or more beyond the life 5 expectancy predicted if no treatment is administered. In another example, a subject responds to treatment with an HSP90 inhibitor, alone or in combination, if the subject has an increased disease-free survival, overall survival or increased time to progression. Several methods can be used to determine if a patient responds to a treatment including the RECIST criteria, as set forth above. 10 "Likely to" or "increased likelihood," as used herein, refers to an increased probability that a response or event will occur with respect to a reference. Thus, in one example, a subject that is likely to respond or survive, or has "an increased responsiveness" or "an increased survival," to a treatment that includes an HSP90 inhibitor has an increased probability of responding, or longer survival, to treatment 15 with an HSP90 inhibitor, alone or in combination with a taxane, relative to a reference subject or group of subjects. In one embodiment, the increased likelihood to respond to the treatment is relative to a subject having a lower HSP90aX level. "Decreased likelihood to" refers to a decreased probability that a response or event will occur with respect to a reference. Thus, a subject that has a "decreased 20 responsiveness" or a "decreased survival" to treatment with an HSP90 inhibitor, alone or in combination with a taxane, has a decreased probability of responding to treatment with an HSP90 inhibitor, alone or in combination with a taxane, relative to a reference subject or group of subjects. In one embodiment, the decreased likelihood to respond to the treatment is relative to a subject having a higher HSP90aX level. It 25 shall be understood that a decreased responsiveness or survival detected in a subject having a lower level of HSP90x is relative to a subject having a higher level of HSP90x, and not an untreated subject. Subjects having both high and low HSP90X can show a higher responsiveness to a treatment that includes an HSP90 inhibitor compared to an untreated subject. 30 "RECIST" shall mean an acronym that stands for "Response Evaluation Criteria in Solid Tumours " and is a set of published rules that define when cancer patients improve ("respond"), stay the same ("stable") or worsen ("progression") during treatments. Response as defined by RECIST criteria have been published, for - 52 - 12041-7037WO / 1014 WO example, at Journal of the National Cancer Institute, Vol. 92, No. 3, Feb. 2, 2000 and RECIST criteria can include other similar published definitions and rule sets. One skilled in the art would understand definitions that go with RECIST criteria, as used herein, such as "PR," "CR," "SD and "PD." 5 A "responder" refers to a subject, e.g., a lung cancer patient, if in response to a cancer therapy (e.g., an HSP90 inhibitor, alone or in combination with a taxane), at least one symptom of cancer in the subject is reduced by about 5%, 10%, 20%, 30%, 40%, 50% or more as determined by any appropriate measure. Other variations of this term, e.g., less responder or decreased responder refer to a subject that shown an 10 intermediate level of response between a responder and a non-responder. A "non-responder" refers to a subject, e.g., a cancer patient if, in response to a cancer therapy (e.g., an HSP90 inhibitor, alone or in combination with a taxane), no symptom of cancer in the subject is reduced by any detectable amount. "Sample," "tissue sample," "patient sample," "patient cell or tissue sample" or 15 "specimen" each refers to a biological sample obtained from a tissue or bodily fluid of a subject or patient. The source of the tissue sample can be solid tissue as from a fresh, frozen and/or preserved organ, tissue sample, biopsy, or aspirate; blood or any blood constituents (e.g., serum, plasma); bodily fluids such as cerebral spinal fluid, whole blood, plasma and serum. The sample can include a non-cellular fraction (e.g., 20 plasma, serum, or other non-cellular body fluid). In one embodiment, the sample is a serum sample. In other embodiments, the body fluid from which the sample is obtained from an individual comprises blood (e.g., whole blood). In certain embodiments, the blood can be further processed to obtain plasma or serum. For example, the sample can be a fine needle biopsy sample, an archival sample (e.g., an 25 archived sample with a known diagnosis and/or treatment history), a histological section (e.g., a frozen or formalin-fixed section, e.g., after long term storage), among others. The term sample includes any material obtained and/or derived from a biological sample, including a polypeptide, and nucleic acid (e.g., genomic DNA, cDNA, RNA) purified or processed from the sample. Purification and/or processing 30 of the sample can involve one or more of extraction, concentration, antibody isolation, sorting, concentration, fixation, addition of reagents and the like. The sample can contain compounds that are not naturally intermixed with the tissue in nature such as preservatives, anticoagulants, buffers, fixatives, nutrients, antibiotics or the like. - 53 - 12041-7037WO / 1014 WO The amount or level of a biomarker, e.g., expression of gene products (e.g., one or more the biomarkers described herein), in a subject is "significantly" higher or lower than the normal amount of a marker, if the amount of the marker is greater or less, respectively, than the normal level by an amount greater than the standard error 5 of the assay employed to assess amount, or at least two, three, four, five, ten or more times that amount. Alternatively, the amount of the marker in the subject can be considered "significantly" higher or lower than the normal amount if the amount is at least about 1.5, two, at least about three, at least about four, or at least about five times, higher or lower, respectively, than the normal amount of the marker. 10 As used herein, "significant event" shall refer to an event in a patient's disease that is important as determined by one skilled in the art. Examples of significant events include, for example, without limitation, primary diagnosis, death, recurrence, the determination that a patient's disease is metastatic, relapse of a patient's disease or the progression of a patient's disease from any one of the above noted stages to 15 another. A significant event can be any important event used to assess OS, TTP and/or using the RECIST or other response criteria, as determined by one skilled in the art. As used herein, "time course" shall refer to the amount of time between an initial event and a subsequent event. For example, with respect to a patient's cancer, time course can relate to a patient's disease and can be measured by gauging 20 significant events in the course of the disease, wherein the first event can be diagnosis and the subsequent event can be metastasis, for example. "Time to progression" or "TTP" refers to a time as measured from the start of the treatment to progression or a cancer or censor. Censoring can come from a study end or from a change in treatment. Time to progression can also be represented as a 25 probability as, for example, in a Kaplein-Meier plot where time to progression can represent the probability of being progression free over a particular time, that time being the time between the start of the treatment to progression or censor. An "underexpression" or "significantly lower level of expression" of products (e.g., the markers set forth herein) refers to an expression level in a test sample that is 30 greater than the standard error of the assay employed to assess expression, for example, at least 1.5, twice, at least three, at least four, at least five, or at least ten or more times less than the expression level of the gene products in a control sample (e.g., a sample from a healthy subject not afflicted with cancer), or the average expression level of gene products in several control samples. - 54 - 12041-7037WO / 1014 WO Various aspects of the present disclosure are described in further detail below. Additional definitions are set out throughout the specification. Predictive and Prognostic Methods 5 The application provides, at least in part, a method for determining whether a subject with a cancer is likely to respond to treatment with an HSP90 inhibitor, alone or in combination with a taxane. In another aspect, provided herein is a method for predicting a time course of disease. In still another aspect, the method is drawn to a method for predicting a probability of a significant event in the time course of the 10 disease. In certain embodiments, the method comprises detecting a biomarker or combination of biomarkers associated with responsiveness to treatment with an HSP90 inhibitor as described herein, alone or in combination, and determining whether the subject is likely to respond to treatment with the HSP90 inhibitor, alone or in combination. 15 In one embodiment, the level of HSP90x is a predictive or prognostic biomarker of responsiveness to a cancer therapy involving HSP90 inhibition. In one embodiment, the level of HSP90x can be detected using a method described herein. HSP90 Polypeptide Detection 20 The amino acid and nucleotide sequences of human heat shock protein HSP 90-alpha are disclosed e.g., in Rebbe, N.F. et al., Gene 53:235-245(1987); Rebbe N.F. et al., J. Biol. Chem. 264:15006-15011(1989); Lees-Miller, S.P. et al., J. Biol. Chem. 264:2431-2437(1989); Yamazaki, M. et al., Agric. Biol. Chem. 54 (12), 3163-3170 (1990); Ozawa, K. et al., Genomics 12 (2), 214-220 (1992); and Ota, T. et al., Nat. 25 Genet. 36:40-45(2004). Exemplary amino acid and nucleotide sequences of human heat shock protein HSP 90-alpha are shown as below. Amino acid sequence of human heat shock protein HSP 90-alpha isoform 1 (NCBI Reference Sequence: NP_001017963.2; GI:153792590) 1 mppcsggdgs tppgpslrdr dcpaqsaeyp rdrldprpgs pseassppfl rsrapvnwyq 30 61 ekaqvflwhl mvsgsttllc lwkqpfhvsa fpvtaslafr qsqgagqhly kdlqpfillr 121 llmpeetqtq dqpmeeeeve tfafqaeiaq lmsliintfy snkeiflrel isnssdaldk 181 iryesltdps kldsgkelhi nlipnkqdrt ltivdtgigm tkadlinnlg tiaksgtkaf 241 mealqagadi smigqfgvgf ysaylvaekv tvitkhndde qyawessagg sftvrtdtge 301 pmgrgtkvil hlkedqteyl eerrikeivk khsqfigypi tlfvekerdk evsddeaeek 35 361 edkeeekeke ekesedkpei edvgsdeeee kkdgdkkkkk kikekyidqe elnktkpiwt 421 rnpdditnee ygefyksltn dwedhlavkh fsvegqlefr allfvprrap fdlfenrkkk - 55 - 12041-7037WO / 1014 WO 481 nniklyvrrv fimdnceeli peylnfirgv vdsedlplni sremlqqski lkvirknlvk 541 kclelftela edkenykkfy eqfskniklg ihedsqnrkk lsellryyts asgdemvslk 601 dyctrmkenq khiyyitget kdqvansafv erlrkhglev iymiepidey cvqqlkefeg 661 ktlvsvtkeg lelpedeeek kkqeekktkf enlckimkdi lekkvekvvv snrlvtspcc 5 721 ivtstygwta nmerimkaqa lrdnstmgym aakkhleinp dhsiietlrq kaeadkndks 781 vkdlvillye tallssgfsl edpqthanri yrmiklglgi deddptaddt saavteempp 841 legdddtsrm eevd (SEQ ID NO:1) Nucleotide sequence of human heat shock protein HSP 90-alpha isoform 1 10 (NCBI Reference Sequence: NM_001017963.2; GI: 153792589) 1 atgcccccgt gttcgggcgg ggacggctcc acccctcctg ggccctccct tcgggacagg 61 gactgtcccg cccagagtgc tgaatacccg cgcgaccgtc tggatccccg cccaggaagc 121 ccctctgaag cctcctcgcc gccgtttctg agaagcaggg cacctgttaa ctggtaccaa 181 gaaaaggccc aagtgtttct ctggcatctg atggtgtctg gatccaccac tctactctgt 15 241 ctctggaaac agcccttcca cgtctctgca ttccctgtca ccgcgtcact ggccttcaga 301 cagagccaag gtgcagggca acacctctac aaggatctgc agccatttat attgcttagg 361 ctactgatgc ctgaggaaac ccagacccaa gaccaaccga tggaggagga ggaggttgag 421 acgttcgcct ttcaggcaga aattgcccag ttgatgtcat tgatcatcaa tactttctac 481 tcgaacaaag agatctttct gagagagctc atttcaaatt catcagatgc attggacaaa 20 541 atccggtatg aaagcttgac agatcccagt aaattagact ctgggaaaga gctgcatatt 601 aaccttatac cgaacaaaca agatcgaact ctcactattg tggatactgg aattggaatg 661 accaaggctg acttgatcaa taaccttggt actatcgcca agtctgggac caaagcgttc 721 atggaagctt tgcaggctgg tgcagatatc tctatgattg gccagttcgg tgttggtttt 781 tattctgctt atttggttgc tgagaaagta actgtgatca ccaaacataa cgatgatgag 25 841 cagtacgctt gggagtcctc agcaggggga tcattcacag tgaggacaga cacaggtgaa 901 cctatgggtc gtggaacaaa agttatccta cacctgaaag aagaccaaac tgagtacttg 961 gaggaacgaa gaataaagga gattgtgaag aaacattctc agtttattgg atatcccatt 1021 actctttttg tggagaagga acgtgataaa gaagtaagcg atgatgaggc tgaagaaaag 1081 gaagacaaag aagaagaaaa agaaaaagaa gagaaagagt cggaagacaa acctgaaatt 30 1141 gaagatgttg gttctgatga ggaagaagaa aagaaggatg gtgacaagaa gaagaagaag 1201 aagattaagg aaaagtacat cgatcaagaa gagctcaaca aaacaaagcc catctggacc 1261 agaaatcccg acgatattac taatgaggag tacggagaat tctataagag cttgaccaat 1321 gactgggaag atcacttggc agtgaagcat ttttcagttg aaggacagtt ggaattcaga 1381 gcccttctat ttgtcccacg acgtgctcct tttgatctgt ttgaaaacag aaagaaaaag 35 1441 aacaacatca aattgtatgt acgcagagtt ttcatcatgg ataactgtga ggagctaatc 1501 cctgaatatc tgaacttcat tagaggggtg gtagactcgg aggatctccc tctaaacata 1561 tcccgtgaga tgttgcaaca aagcaaaatt ttgaaagtta tcaggaagaa tttggtcaaa 1621 aaatgcttag aactctttac tgaactggcg gaagataaag agaactacaa gaaattctat 1681 gagcagttct ctaaaaacat aaagcttgga atacacgaag actctcaaaa tcggaagaag 40 1741 ctttcagagc tgttaaggta ctacacatct gcctctggtg atgagatggt ttctctcaag 1801 gactactgca ccagaatgaa ggagaaccag aaacatatct attatatcac aggtgagacc 1861 aaggaccagg tagctaactc agcctttgtg gaacgtcttc ggaaacatgg cttagaagtg 1921 atctatatga ttgagcccat tgatgagtac tgtgtccaac agctgaagga atttgagggg 1981 aagactttag tgtcagtcac caaagaaggc ctggaacttc cagaggatga agaagagaaa 45 2041 aagaagcagg aagagaaaaa aacaaagttt gagaacctct gcaaaatcat gaaagacata 2101 ttggagaaaa aagttgaaaa ggtggttgtg tcaaaccgat tggtgacatc tccatgctgt 2161 attgtcacaa gcacatatgg ctggacagca aacatggaga gaatcatgaa agctcaagcc 2221 ctaagagaca actcaacaat gggttacatg gcagcaaaga aacacctgga gataaaccct 2281 gaccattcca ttattgagac cttaaggcaa aaggcagagg ctgataagaa cgacaagtct - 56 - 12041-7037WO / 1014 WO 2341 gtgaaggatc tggtcatctt gctttatgaa actgcgctcc tgtcttctgg cttcagtctg 2401 gaagatcccc agacacatgc taacaggatc tacaggatga tcaaacttgg tctgggtatt 2461 gatgaagatg accctactgc tgatgatacc agtgctgctg taactgaaga aatgccaccc 2521 cttgaaggag atgacgacac atcacgcatg gaagaagtag actaa (SEQ ID NO:2) 5 Amino acid sequence of human heat shock protein HSP 90-alpha isoform 2 (NCBI Reference Sequence: NP_005339; GI:154146191) 1 mpeetqtqdq pmeeeevetf afqaeiaqlm sliintfysn keiflrelis nssdaldkir 61 yesltdpskl dsgkelhinl ipnkqdrtlt ivdtgigmtk adlinnlgti aksgtkafme 10 121 alqagadism igqfgvgfys aylvaekvtv itkhnddeqy awessaggsf tvrtdtgepm 181 grgtkvilhl kedqteylee rrikeivkkh sqfigypitl fvekerdkev sddeaeeked 241 keeekekeek esedkpeied vgsdeeeekk dgdkkkkkki kekyidqeel nktkpiwtrn 301 pdditneeyg efyksltndw edhlavkhfs vegqlefral lfvprrapfd lfenrkkknn 361 iklyvrrvfi mdnceelipe ylnfirgvvd sedlplnisr emlqqskilk virknlvkkc 15 421 lelftelaed kenykkfyeq fskniklgih edsqnrkkls ellryytsas gdemvslkdy 481 ctrmkenqkh iyyitgetkd qvansafver lrkhgleviy miepideycv qqlkefegkt 541 lvsvtkegle lpedeeekkk qeekktkfen lckimkdile kkvekvvvsn rlvtspcciv 601 tstygwtanm erimkaqalr dnstmgymaa kkhleinpdh siietlrqka eadkndksvk 661 dlvillyeta llssgfsled pqthanriyr miklglgide ddptaddtsa avteempple 20 721 gdddtsrmee vd (SEQ ID NO:3) Nucleotide sequence of human heat shock protein HSP 90-alpha isoform 2 (NCBI Reference Sequence: NM_005348.3; GI:154146190) 1 atgcctgagg aaacccagac ccaagaccaa ccgatggagg aggaggaggt tgagacgttc 25 61 gcctttcagg cagaaattgc ccagttgatg tcattgatca tcaatacttt ctactcgaac 121 aaagagatct ttctgagaga gctcatttca aattcatcag atgcattgga caaaatccgg 181 tatgaaagct tgacagatcc cagtaaatta gactctggga aagagctgca tattaacctt 241 ataccgaaca aacaagatcg aactctcact attgtggata ctggaattgg aatgaccaag 301 gctgacttga tcaataacct tggtactatc gccaagtctg ggaccaaagc gttcatggaa 30 361 gctttgcagg ctggtgcaga tatctctatg attggccagt tcggtgttgg tttttattct 421 gcttatttgg ttgctgagaa agtaactgtg atcaccaaac ataacgatga tgagcagtac 481 gcttgggagt cctcagcagg gggatcattc acagtgagga cagacacagg tgaacctatg 541 ggtcgtggaa caaaagttat cctacacctg aaagaagacc aaactgagta cttggaggaa 601 cgaagaataa aggagattgt gaagaaacat tctcagttta ttggatatcc cattactctt 35 661 tttgtggaga aggaacgtga taaagaagta agcgatgatg aggctgaaga aaaggaagac 721 aaagaagaag aaaaagaaaa agaagagaaa gagtcggaag acaaacctga aattgaagat 781 gttggttctg atgaggaaga agaaaagaag gatggtgaca agaagaagaa gaagaagatt 841 aaggaaaagt acatcgatca agaagagctc aacaaaacaa agcccatctg gaccagaaat 901 cccgacgata ttactaatga ggagtacgga gaattctata agagcttgac caatgactgg 40 961 gaagatcact tggcagtgaa gcatttttca gttgaaggac agttggaatt cagagccctt 1021 ctatttgtcc cacgacgtgc tccttttgat ctgtttgaaa acagaaagaa aaagaacaac 1081 atcaaattgt atgtacgcag agttttcatc atggataact gtgaggagct aatccctgaa 1141 tatctgaact tcattagagg ggtggtagac tcggaggatc tccctctaaa catatcccgt 1201 gagatgttgc aacaaagcaa aattttgaaa gttatcagga agaatttggt caaaaaatgc 45 1261 ttagaactct ttactgaact ggcggaagat aaagagaact acaagaaatt ctatgagcag 1321 ttctctaaaa acataaagct tggaatacac gaagactctc aaaatcggaa gaagctttca 1381 gagctgttaa ggtactacac atctgcctct ggtgatgaga tggtttctct caaggactac 1441 tgcaccagaa tgaaggagaa ccagaaacat atctattata tcacaggtga gaccaaggac - 57 - 12041-7037WO /1014 WO 1501 caggtagcta actcagcctt tgtggaacgt cttcggaaac atggcttaga agtgatctat 1561 atgattgagc ccattgatga gtactgtgtc caacagctga aggaatttga ggggaagact 1621 ttagtgtcag tcaccaaaga aggcctggaa cttccagagg atgaagaaga gaaaaagaag 1681 caggaagaga aaaaaacaaa gtttgagaac ctctgcaaaa tcatgaaaga catattggag 5 1741 aaaaaagttg aaaaggtggt tgtgtcaaac cgattggtga catctccatg ctgtattgtc 1801 acaagcacat atggctggac agcaaacatg gagagaatca tgaaagctca agccctaaga 1861 gacaactcaa caatgggtta catggcagca aagaaacacc tggagataaa ccctgaccat 1921 tccattattg agaccttaag gcaaaaggca gaggctgata agaacgacaa gtctgtgaag 1981 gatctggtca tcttgcttta tgaaactgcg ctcctgtctt ctggcttcag tctggaagat 10 2041 ccccagacac atgctaacag gatctacagg atgatcaaac ttggtctggg tattgatgaa 2101 gatgacccta ctgctgatga taccagtgct gctgtaactg aagaaatgcc accccttgaa 2161 ggagatgacg acacatcacg catggaagaa gtagactaa (SEQ ID NO:4) Anti-HSP90-alpha antibodies can be generated using the sequences and 15 techniques disclosed herein. Numerous anti-HSP 90-alpha antibodies are commercially available. Exemplary anti-HSP 90-alpha antibodies that are commercially available include, but not limited to, antibodies from Enzo Life Sciences (e.g., Cat. Nos. ADI-SPP-776; ADI-SPP-771; ADI-SPA-840 (9D2); ADI SPA-839 (k41009); ADI-EKS-895; ALX-804-808-C100 (H90-10)); Abbiotech (e.g., 20 Cat. No. 250702), Abcam (e.g., Cat. Nos. ab79849 (2G5.G3), ab59459 (D7a), ab74248, ab109248 (EPR3953)); AbD Serotec (e.g., Cat. Nos. P07900, AHP1339); AbFrontier (e.g., Cat. No. LF-PA41463); Abnova (e.g., Cat. Nos. P3387, MAB1092 (4F10), MAB2186 (2G5.G3), MAB2187 (4F3.E8), MAB2196 (BB70), MAB2197 (D7alpha), MAB6619 (Hyb-K41009), MAB6631 (Hyb-K41220), PAB10218, 25 PAB10219, PAB13569, PAB18294, MAB1092 (4F10)); Acris (e.g., Cat. Nos. AM03150PU (Hyb-K41220A), AM26034PU-N (MBH90AB), AM09018PU (4F10), AP23429PU-N, SM5068 (3B6), AP22747PU-N, AM03143PU-N (Hyb-K41009), AM03152PU (D7alpha), AM12010PU-N (Hyb-K41009), AM12023PU (2G5.G3), AP00517PU-N, AP05686PU-N, AP06175PU-N, AP09321PU-N, AP09353PU-N, 30 SP5443P, SM5069 (3G3), AM03144PU (8D3)); Aviva System Biology (e.g., Cat. Nos. P100674_P050, ARP30184_PO50); Biorbyt (e.g., Cat. Nos. orbl8228, orblO850, orblO851, orb15793, orb15794, orbl7010); Cayman Chemical (e.g., Cat. Nos. 10011441 (D7a), 10011427 (K41009)); Cell Signaling (e.g., Cat. Nos. 4877 (C45G5), 4875 (E289), 4874); Epitomics (e.g., Cat. Nos. 3363-1 (EPR3953), 2877-1 35 (EPNCIR102), 3670-1 (EPR5355)); GeneTex (e.g., Cat. Nos. GTX73047, GTX82095); Genway (e.g., Cat. Nos. 18-272-198252, 18-821-485163, 18-821 485164, 20-821-485051, 20-821-485052, 20-821-485022, 20-821-485021, 20-821 485012, 20-821-485011, 20-002-35056 (4F10), 20-272-190867 (2D12), 20-272 - 58 - 12041-7037WO / 1014 WO 192231 (S88), 20-614-460339, 20-821-485066, 18-464-436550, 18-464-435980, 20 511-242207); LifeSpan BioSciences (e.g., Cat. Nos. LS-C108955, LS-C108974, LS C108965, LS-B375, LS-B4556, LS-C15713, LS-C36625, LS-C36617, LS-C118489, LS-C88632, LS-C88628, LS-C121936, LS-C48189, LS-C82985, LS-C48372, LS 5 C112338, LS-C67309, LS-C15724, LS-C67306, LS-C24176, LS-C18695, LS C63283, LS-C15729, LS-C15714, LS-C36616, LS-C15728, LS-C15726, LS-C67312, LS-C67313, LS-C15725, LS-C15727); MBL (e.g., Cat. No. SR-840F(9d2)); Millipore (e.g., Cat. No. 07-2174); Novus (e.g., Cat. Nos. NB120-1429 (S88), NB100-1972 (AC88), NB 110-96872 (D7alpha), NB 120-2928, NB 110-61641 (Hyb-K41009), 10 NBP1-67601, NBP1-45630, NB110-96430, NB120-19104, NBP1-47564, NB110 96870 (Hyb-K41220A), NBP1-04301, NB120-5455); ProSci (e.g., Cat. No. XW 7769); Prospec (e.g., Cat. No. ANT-398 (P4F1OAT)); QED Bioscience (e.g., Cat. No. 11112); Raybiotech (e.g., Cat. No. DS-PB-02625); Rockland Immunochemicals (e.g., Cat. No. 600-401-929); Santa Cruz Biotechnology (e.g., Cat. Nos. sc-59577 (AC88), 15 sc-59578 (S88), sc-12833 (aE-17), sc-13119 (F-8), sc-7947 (H-114), sc-1055 (N-17), sc-69703 (4F10), sc-33755 (at-115), sc-101701 (Ser 254), sc-51966 (1A6), sc-101494 (AC-16)); Sigma-Aldrich (e.g., Cat. No. GW21241); StressMarq Biosciences (e.g., Cat. Nos. SMC-147 (2G5.G3), SMC-108 (Hyb-K41009)); Thermo Scientific (e.g., Cat. Nos. MA5-14866 (K.846.8), PA5-17402, PA5-17610) 20 Detection of Other Biomarkers In one embodiment, the method provided herein comprises the detection and evaluation of more than one biomarker, such as, the evaluation of HSP90aX levels as described herein and one or more of other biomarkers provided herein. For example, 25 in one embodiment, the method provided herein comprises the evaluation of HSP90X levels as described herein (e.g., as compared to a predetermined value) in a subject, and the determination of a biomarker provided herein in the same subject (e.g., presence of or alteration of, one or more of the oncogene biomarkers provided herein; or e.g., a biomarker for hypoxia). 30 In one embodiment, the subject sample includes, but is not limited to, one or more of tumor tissue, blood, urine, stool, lymph, cerebrospinal fluid, circulating tumor cells, bronchial lavage, peritoneal lavage, exudate, effusion, and sputum. In certain - 59 - 12041-7037WO / 1014 WO embodiments, the tumor tissue is tumor tissue that is in the subject or that is removed from the subject. In one embodiment, the method provided herein further comprises the step of measuring one or more marker(s) for hypoxia in a subject, such as, e.g., hypoxia 5 inducible factor (HIF) or lactate dehydrogenase (LDH), among others. See, e.g., WO 2012/068487, which is incorporated herein by reference. In certain embodiments, a high level of HSP90x in a subject in combination with a high level of hypoxia is indicative of increased responsiveness to a therapy described herein (e.g., a combination therapy comprising an HSP90 inhibitor and a taxane). 10 In one embodiment, provided herein is a method for selection of a subject for treatment with a therapy described herein (e.g., a combination therapy comprising an HSP90 inhibitor and a taxane), based on high levels of lactate dehydrogenase (LDH) in a cell, e.g., a cancerous cell, or in a subject sample. In certain embodiments, the level of hypoxia is determined by detecting the 15 activity level or expression level of one or more hypoxia modulated polypeptides. In certain embodiments, the activity level or expression level of the one or more hypoxia modulated polypeptides are up regulated in the sample. The level of hypoxia can be determined by any method known in the art including, but not limited to, detecting the activity level or expression level of one or more hypoxia modulated polypeptides or 20 using detection methods selected from the group consisting of detection of activity or expression of at least one isoform or subunit of lactate dehydrogenase (LDH), at least one isoform or subunit of hypoxia inducible factor (HIF), at least one pro-angiogenic form of vascular endothelial growth factor (VEGF), phosphorylated VEGF receptor (pKDR) 1, 2, and 3; neurolipin 1 (NRP-1), pyruvate dehydrokinase (PDH-K), 25 ornithine decarboxylase (ODC), glucose transporter- 1 (GLUT-1), glucose transporter-2 (GLUT-2), tumor size, blood flow, EF5 binding, pimonidazole binding, PET scan, and probe detection of hypoxia level. In certain embodiments, the isoform or subunit of LDH comprises one or more of: LDH5, LDH4, LDH3, LDH2, LDH1, LDHA and LDHB; or any combination 30 thereof including total LDH. In certain embodiments, the isoform of HIF comprises one or more of: HIF- la, HIF-1 P, HIF-2a, and HIF-2p; or any combination thereof including total HIF-1 and/or HIF-2. In certain embodiments, the pro-angiogenic - 60 - 12041-7037WO / 1014 WO isoform of VEGF is any VEGF-A isoform, or any combination of VEGF-A isoforms including total VEGF-A. In certain embodiments, detection of a high level of activity or expression of at least one LDH isoform or subunit comprises detection of an LDH activity or 5 expression level of an LDH, selected from the group consisting of: total LDH, LDH5, LDH4, LDH5 plus LDH4, LDH5 plus LDH4 plus LDH3, and LDHA. In certain embodiments, detection of a high level of hypoxia comprises detection of a change in a ratio or levels of activity or expression or a change in a ratio of normalized levels of activity or expression of hypoxia modulated polypeptides. In 10 certain embodiments, a high level of hypoxia comprises a ratio or a normalized ratio of 1.0 or more of the ULN, wherein the ratio or normalized ratio is selected from the group consisting of the LDHA to LDHB, LDH5 or LDH4 to LDH1, LDH5 or LDH4 to total LDH, LDH5 and LDH4 to LDH1, LDH5 and LDH4 to total LDH, LDH5, LDH4, and LDH3 to LDH1, and LDH5, LDH4, and LDH3 to total LDH. 15 In certain embodiments, the method further includes identifying a subject as having a high level of hypoxia. In other embodiments, the methods further include evaluation, e.g., cytogenetic screening, of biological tissue sample from a subject, e.g., a patient who has been diagnosed with or is suspected of having cancer (e.g., presents with 20 symptoms of cancer) to detect one or more ALK alterations, e.g., ALK mutations. Representative, non-limiting examples of cytogenetic abnormalities that are screened include one or more of the following: EML4-ALK fusions, KIF5B-ALK fusions, TGF-ALK fusions, NPM-ALK fusions, ALK gene copy number changes, and ALK point mutations comprising one or more of F12451/L, L1204F, A1200V, L1196M, 25 11170S, T1151M, R1275Q, F1174V/C/L, T10871, and K1062M, as described herein. In other embodiments, alterations in a MAPK pathway gene can be detected. "MAPK pathway gene(s)," as used herein, refers to genes that are directly and/or indirectly involved in intracellular signaling via mitogen activated protein kinases (MAPK). In some embodiments, this direct and/or indirect involvement can comprise 30 genes upstream and/or downstream of MAPK. MAP kinases are well known in the art to comprise important mediators of cancer-related disease mechanisms (Chen et al., Chem Rev (2001) 101:2449-76; Pearson et al., Endocr. Rev. (2001) 22:153-83; English et al., Trends Pharmacol. Sci. (2002) 23:40-45; Kohno et al., Prog. Cell Cycle Res. (2003) 5:219-24; and Sebolt-Leopold, Oncogene (2000) 19:6594-99). One of the - 61 - 12041-7037WO / 1014 WO MAPK pathways enables the transmission of signals from extracellular signals, such as epidermal growth factor (EGF) and vascular endothelial derived growth factor (VEGF), which bind to a corresponding receptor in the cell membrane, EGFR, HER, and VEGFR, respectively, which sends the signal on to the cell nucleus via 5 intermediary kinases and kinase targets. In one embodiment, a MAPK pathway comprises RAS, RAF, MEK, and ERK (MAPK) (e.g., Ras, Raf-1, A-Raf, B-Raf (BRAF), MEK1 and/or MEK2, which are collectively referred to herein as MEK1/2, and ERK1 and/or ERK2, which are collectively referred to herein as ERK1/2. In some embodiments, such MAPK pathways further comprise MAPK target genes as 10 Mnkl, Rsk, Ets, Elk-i, and Sap-i. In other embodiments, the methods further include evaluation, e.g., cytogenetic screening, of biological tissue sample from a subject, e.g., a patient who has been diagnosed with or is suspected of having cancer (e.g., presents with symptoms of cancer) to detect one or more alteration in, e.g., ALK, RAS (e.g., one or 15 more of H-Ras, N-Ras, or K-Ras), EGFR, PIK3CA, RAF (e.g., one or more of A-Raf, B-Raf (BRAF) or C-Raf), PTEN, AKT, TP53 (p53), CTNNB1 (beta-catenin), APC, KIT, JAK2, NOTCH, FLT3, MEK, ERK, RSK, ETS, ELK-i, SAP-1, CDKN2a, KEAPi, NFE2L2, HLA-A, p13K, ErbB-2, CDK, DDR2, PDGFR, FGFR, retinoblastoma 1, or cullin 3. Examples of gene mutations are described in e.g., The 20 Catalogue of Somatic Mutations in Cancer (COSMIC) (http://www.sanger.ac.uk/genetics/CGP/cosmic/). Examples of EGFR mutations are described in e.g., Couzin J., (2004) Science 305:1222-1223; Fukuoka, M. et al., (2003) J. Clin. Oncol. 21:2237-46; Lynch et al., (2004) NEJM 350(21):2129-2139; Paez et al. (2004) Science 304:1497-1500; Pao, W. 25 et al. Proc Natl Acad Sci U S A. (2004) 101(36):13306-11; Gazdar A. F. et al., Trends Mol Med.(2004) 10(10):481-6; Huang S. F. et al. (2004) Clin. Cancer Res. 10(24):8195-203; Couzin J. Science (2004) 305(5688):1222-3; Sordella R. et al. (2004) 305(5687):1163-7; Kosaka T. et al. (2004) Cancer Res. 64(24):8919-23; Marchetti A. et al. J Clin Oncol. (2005) 23(4):857-65; Tokumo M. et al. (2005) Clin 30 Cancer Res. 11(3):1167-1173; Han S. W. et al. (2005) J Clin Oncol. 23(11):2493 501; Mitsudomi T. et al. (2005) J Clin Oncol. 23(11):2513-20; Shigematsu H. et al. J. Natl. Cancer Inst. 97(5):339-46; Kim K. S. et al., (2005) Clin Cancer Res.11(6):2244 51; Cappuzzo F. et al. (2005) JNatl Cancer Inst. 97(9):643-55; Cortes-Funes H. et al. Ann Oncol. (2005) 16(7):1081-6; Sasaki H. et al. (2005) Clin Cancer Res. 11(8):2924 - 62 - 12041-7037WO / 1014 WO 9; Chou T. Y. et al., (2005) Clin Cancer Res. 11(10):3750-7; Pao W. et al. (2005) PLoS Med. 2(3):e73; Sasaki H. et al. (2005) Int J Cancer. 118(1):180-4; Eberhard D. A. et al. (2005) J Clin Oncol. 23(25):5900-9; Takano T. et al. (2005) J Clin Oncol. 23(28):6829-37; Tsao M. S. et al., (2005) N. Engl. J. Med. 353(2):133-44; Mu X. L. et 5 al. (2005) Clin Cancer Res. 11(12):4289-94; Sonobe M. et al. (2005) Br. J. Cancer, 93(3):355-63; Taron M. et al. (2005) Clin Cancer Res. 11(16):5878-85; Mukohara T. et al., (2005) J Natl Cancer Inst. 97(16):1185-94; Zhang X. T. et al. (2005) Oncol. 16(8):1334-42. Exemplary alterations in an EGFR gene or gene product, include but are not limited to, an EGFR exon deletion (e.g., EGFR exon 19 Deletion), and/or exon 10 mutation (e.g., an L858R/T790M EGFR mutation). Other exemplary alterations include, but are not limited to, EGFR_ D770_N771>AGG; EGFR_D770_N771insG; EGFR_D770_N77linsG; EGFR_D770_N77linsN; EGFR_E709A; EGFR E709G; EGFR_709H; EGFRE709K; EGFRE709V; EGFRE746_A750del; EGFRE746_A750del, T751A; EGFRE746_A750del, V ins; EGFRE746_T75ldel, 15 I ins; EGFR_E746_T751del, S752A; EGFRE746_T751del, S752D; EGFRE746_T751 del, V ins; EGFR__G719A; EGFRG719C; EGFRG719S: EGFRH773_V774insH; EGFR__H773_V774insNPH; EGFR H773_V774insPH; EGFRH773>NPY; EGFRL747_E749del; EGFRL747_E749del, A750P; EGFRL747_S752del; EGFRL747_S752del, P753S; EGFRL747_S752del, Q ins; 20 EGFRL747_T750del, P ins; EGFRL747_T751del; EGFRL858R; EGFRL861Q; EGFRM766_A767insAI; EGFRP772_H773insV; EGFR S752_1759del; EGFRS7681; EGFRT790M; EGFR_V769_D770insASV; EGFRV769_D770insASV: and EGFRV774_C775insHV. Examples of Ras mutations, include but are not limited to, K-Ras, H-Ras 25 and/or N-Ras include, for example, mutations in codon 12, 13 and/or 61, including but not limited to, G12A, G12N, G12R, G12C, G12S, G12V, G13N and Q61R. Examples of NRAS mutations are described in e.g., Bacher U. et al. (2006) Blood 107:3847-53; Banerji U. et al. (2008) Mol. Cancer Ther. 7:737-9. Examples of K-Ras mutations are described in e.g., Tang W. Y. et al. (1999) Br. J. Cancer, 81(2):237-41; 30 Burmer G. C. et al. (1989) Proc. Natl. Acad. Sci. U.S.A. 86(7): 2403-7; Almoguera C. et al. (1988) Cell 53(4): 549-54; Tam I. Y. et al. (2006), Clin. Cancer Res. 12(5): 1647-53; and Ratner, E. et al. (2010) Cancer Res 70(16): OF1-OF7. Non-limiting examples of alterations in a KRAS gene is selected from the group consisting of KRAS_G12C, KRASG12R, KRAS_G12D,. KRASG12A, KRASG12S, - 63 - 12041-7037WO / 1014 WO KRAS_G12V, KRASG13D, KRAS_G13S, KRASG13C, KRAS_G13V, KRASQ61H, KRASQ61R, KRASQ61P, KRASQ61L, KRASQ61K, KRASQ61E, KRASA59T and KRASG12F. Examples of PIK3CA mutations are described in e.g., Samuels Y. et al. (2004) 5 Science 304(5670):554; Kurtis E. et al. (2004) Cancer Biology & Therapy 3(8):772 775; Stemke-Hale K. et al. (2008) Cancer Res. 68(15):6084-91. Examples of mutations in RAF (e.g., one or more of A-Raf, B-Raf (BRAF) or C-Raf) gene or gene product include, but are not limited to, a mutation in codon 600 of B-Raf.Examples of BRAF mutations are described in e.g., Davies H. et al. (2002) 10 Nature 417: 949-954. Exemplary alterations in the BRAF gene or gene product, include but are not limited to, BRAFD594G, BRAF D594V, BRAFF468C, BRAFF595L, BRAF G464E, BRAFG464R, BRAFG464V, BRAFG466A, BRAFG466E, BRAFG466R, BRAF G466V, BRAF G469A, BRAFG469E, BRAFG469R, BRAFG469R, BRAFG469S, BRAFG469V, BRAFG596R, 15 BRAFK601E, BRAFK601N, BRAF L597Q, BRAFL597R, BRAFL597S, BRAFL597V, BRAFT5991, BRAFV600E, BRAFV600K, BRAF V600L, and BRAFV600R. Examples of PTEN mutations are described in, e.g., Minaguchi T. et al. (2001) Clin Cancer Res. 7(9):2636-42; Latta E. et al. (2002) Curr. Opin. Obstet. Gynecol. 20 14(1):59-65; Eng C. (2003) Hum. Mutat. 22(3):183-98; Konopka B. et al. (2002) Cancer Lett. 178(1):43-51; Stemke-Hale K. et al. (2008) Cancer Res. 68(15):6084-91. Examples of AKT mutations are described in, e.g., Stemke-Hale K. et al. (2008) Cancer Res. 68(15):6084-91; Davies M. A. et al. (2008) Br. J. Cancer.99(8):1265-8; Askham J. M. (2010) Oncogene 29(1):150-5; Shoji K. et al 25 (2009) BrJ Cancer. 101(1):145-8. Examples of TP53 mutations are described in, e.g., Soussi T. (2007) Cancer Cell 12(4):303-12; Cheung K. J. (2009) Br. J. Haematol. 146(3):257-69; Pfeifer G. P. et al. (2009) Hum Genet. 125(5-6):493-506; Petitjean A. et al. (2007) Oncogene 26(15):2157-65. 30 Examples of CTNNB 1 (beta-catenin)mutations are described in, e.g., Polakis P. et al. (2000) Genes Dev. 14(15):1837-51; Miyaki M. et al. (1999) Cancer Res.59(18):4506-9; Tejpar S. et al. (1999) Oncogene 18(47):6615-20; Garcia-Rostan G. et al. (1999) Cancer Res. 59(8):1811-5; Chan E. F. et al. (1999) Nat Genet. - 64 - 12041-7037WO / 1014 WO 21(4):410-3; Legoix P. et al. (1999) Oncogene 18(27):4044-6; Mirabelli-Primdahl L. et al. (1999) Cancer Res. 59(14):3346-51. Examples of NOTCH mutations are described in, e.g., Collins B. J. et al. (2004) Semin Cancer Biol. 14(5):357-64; Callahan R. et al. (2001) J. Mammary 5 Gland Biol. Neoplasia.6(1):23-36; Mansour M. R. et al. (2006) Leukemia 20:537-539; de Celis J. F. et al. (1993) Proc Natl Acad Sci U S A. 90(9):4037-41. Examples of FLT3 mutations are described in, e.g., Kiyoi H. et al. (2006) Methods Mol. Med. 125:189-97; Small D. (2006) Hematology Am. Soc. Hematol. Educ. Program.2006:17 8-84; Kiyoi H. et al. (2006) Int J Hematol. 2006 10 May;83(4):301-8; Schnittger S. et al. (2004) Acta Haematol. 112(1-2):68-78. Examples of ERBB2 mutations are described in, e.g., U.S. Patent Application Publication Number 2008/0206248; Lee J. W. et al. (2006) Clin Cancer Res. 12(1):57-61; Lee J. W. et al. (2006) Cancer Lett. 237(1):89-94; Cancer Genome Atlas Research Network (2008) Nature 455(7216):1061-8. 15 Examples of HSP90AA1 mutations are described in, e.g., Cancer Genome Atlas Research Network (2008) Nature 455(7216):1061-8; Parsons D. W. et al. (2008) Science 321;1807-12; Sjablom T. et al. (2006) Science 314;268-74. Examples of HSP90AB 1 mutations are described in, e.g., Dalgliesh G. L. et al. (2010) Nature 463;360-3; Parsons D. W. et al. (2008) Science 321;1807-12; Sjablom 20 T. et al. (2006) Science 314;268-74. Examples NF1 mutations are described in, e.g., Thomson S. A. et al. (2002) J Child Neurol. 17(8):555-61; Bottillol. et al. (2009) J Pathol. 217(5):693-701; Kluwe L. et al. (2003) J Med Genet. 40(5):368-71. Examples of STK11 (or LKB1) mutations are described in, e.g., Resta N. et al. 25 (1998) Cancer Res. 58(21):4799-801; Nishioka Y. et al. (1999) Jpn. J. Cancer Res. 90(6):629-32; Marignani P. A. (2005) J. Clin. Pathol.58(1):15-9; Katajisto P. et al. (2007) Biochim. Biophys. Acta. 1775(1):63-75. Any oncogenic alteration known in the art can be evaluated or treated using the methods provided herein are known in the art. 30 The results of the screening method and the interpretation thereof are predictive of the patient's response to treatment with HSP90 inhibiting agents (e.g., IPI-493 and/or IPI-504), alone or in combination. According to the present disclosure, the presence of one or oncogenic alterations in a gene or gene product, e.g., an ALK and/or a MAPK pathway mutation, is indicative that treatment with - 65 - 12041-7037WO / 1014 WO HSP90 inhibitor (e.g., IPI-493 and/or IPI-504), alone or in combination, will provide enhanced therapeutic benefit against the cancer cells relative to those of patients not having the mutation. As discussed further herein, a variety of methods and techniques that are well 5 known in the art can be used for the screening analysis, including metaphase cytogenetic analysis by standard karyotype methods, FISH, spectral karyotyping or MFISH, and comparative genomic hybridization. Detection Methods 10 Methods to measure biomarker polypeptides, include, but are not limited to: Western blot, immunoblot, enzyme-linked immunosorbant assay (ELISA), radioimmunoassay (RIA), immunoprecipitation, surface plasmon resonance, chemiluminescence, fluorescent polarization, phosphorescence, immunohistochemical analysis, liquid chromatography mass spectrometry (LC-MS), matrix-assisted laser 15 desorption/ionization time-of-flight (MALDI-TOF) mass spectrometry, microcytometry, microarray, microscopy, fluorescence activated cell sorting (FACS), flow cytometry, laser scanning cytometry, hematology analyzer and assays based on a property of the protein including but not limited to DNA binding, ligand binding, or interaction with other protein partners. 20 The activity or level of a marker protein can also be detected and/or quantified by detecting or quantifying the expressed polypeptide. The polypeptide can be detected and quantified by any of a number of means well known to those of skill in the art. These can include analytic biochemical methods such as electrophoresis, capillary electrophoresis, high performance liquid chromatography (HPLC), thin layer 25 chromatography (TLC), hyperdiffusion chromatography, and the like, or various immunological methods such as fluid or gel precipitin reactions, immunodiffusion (single or double), immunoelectrophoresis, radioimmunoassay (RIA), enzyme-linked immunosorbent assays (ELISAs), immunofluorescent assays, Western blotting, immunohistochemistry and the like. A skilled artisan can readily adapt known 30 protein/antibody detection methods for use in determining the expression level of one or more biomarkers in a serum sample. Another agent for detecting a polypeptide provided herein is an antibody capable of binding to a polypeptide corresponding to a marker provided herein, e.g., an antibody with a detectable label. Antibodies can be polyclonal or monoclonal. An - 66 - 12041-7037WO / 1014 WO intact antibody, or a fragment thereof (e.g., Fab or F(ab') 2 ) can be used. The term "labeled," with regard to the probe or antibody, is intended to encompass direct labeling of the probe or antibody by coupling (i.e., physically linking) a detectable substance to the probe or antibody, as well as indirect labeling of the probe or 5 antibody by reactivity with another reagent that is directly labeled. Examples of indirect labeling include detection of a primary antibody using a fluorescently labeled secondary antibody and end-labeling of a DNA probe with biotin such that it can be detected with fluorescently labeled streptavidin. In another embodiment, the antibody is labeled, e.g., a radio-labeled, 10 chromophore-labeled, fluorophore-labeled, or enzyme-labeled antibody. In another embodiment, an antibody derivative (e.g., an antibody conjugated with a substrate or with the protein or ligand of a protein-ligand pair {e.g., biotin-streptavidin} ), or an antibody fragment (e.g., a single-chain antibody, an isolated antibody hypervariable domain, etc.) which binds specifically with a protein corresponding to the marker, 15 such as the protein encoded by the open reading frame corresponding to the marker or such a protein which has undergone all or a portion of its normal post-translational modification, is used. Immunohistochemistry or IHC refers to the process of localizing antigens (e.g. proteins) in cells of a tissue section exploiting the principle of antibodies binding 20 specifically to antigens in biological tissues. Specific molecular markers are characteristic of particular cellular events such as proliferation or cell death (apoptosis). IHC is also widely used in research to understand the distribution and localization of biomarkers and differentially expressed proteins in different parts of a biological tissue. Visualizing an antibody-antigen interaction can be accomplished in 25 a number of ways. In the most common instance, an antibody is conjugated to an enzyme, such as peroxidase, that can catalyze a color-producing reaction. Alternatively, the antibody can also be tagged to a fluorophore, such as fluorescein, rhodamine, DyLight Fluor or Alexa Fluor. Proteins from cells can be isolated using techniques that are well known to 30 those of skill in the art. The protein isolation methods employed can, for example, be such as those described in Harlow and Lane (Harlow and Lane, 1988, Antibodies: A Laboratory Manual, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, New York). - 67 - 12041-7037WO / 1014 WO In one format, antibodies, or antibody fragments, can be used in methods such as Western blots or immunofluorescence techniques to detect the expressed proteins. In such uses, one can immobilize either the antibody or proteins on a solid support. Suitable solid phase supports or carriers include any support capable of binding an 5 antigen or an antibody. Well-known supports or carriers include glass, polystyrene, polypropylene, polyethylene, dextran, nylon, amylases, natural and modified celluloses, polyacrylamides, gabbros, and magnetite. One skilled in the art will know many other suitable carriers for binding antibody or antigen, and will be able to adapt such support for use with the present 10 disclosure. For example, protein isolated from cells can be run on a polyacrylamide gel electrophoresis and immobilized onto a solid phase support such as nitrocellulose. The support can then be washed with suitable buffers followed by treatment with the detectably labeled antibody. The solid phase support can then be washed with the buffer a second time to remove unbound antibody. The amount of bound label on the 15 solid support can then be detected by conventional means. Means of detecting proteins using electrophoretic techniques are well known to those of skill in the art (see generally, R. Scopes (1982) Protein Purification, Springer-Verlag, N.Y.; Deutscher, (1990) Methods in Enzymology Vol. 182: Guide to Protein Purification, Academic Press, Inc., N.Y.). 20 In another embodiment, Western blot (immunoblot) analysis is used to detect and quantify the presence of a polypeptide in the sample. This technique generally comprises separating sample proteins by gel electrophoresis on the basis of molecular weight, transferring the separated proteins to a suitable solid support, (such as a nitrocellulose filter, a nylon filter, or derivatized nylon filter), and incubating the 25 sample with the antibodies that specifically bind a polypeptide. The anti-polypeptide antibodies specifically bind to the polypeptide on the solid support. These antibodies can be directly labeled or alternatively can be subsequently detected using labeled antibodies (e.g., labeled sheep anti-human antibodies) that specifically bind to the anti-polypeptide. 30 In another embodiment, the polypeptide is detected using an immunoassay. As used herein, an immunoassay is an assay that utilizes an antibody to specifically bind to the analyte. The immunoassay is thus characterized by detection of specific binding of a polypeptide to an anti-antibody as opposed to the use of other physical or chemical properties to isolate, target, and quantify the analyte. - 68 - 12041-7037WO / 1014 WO The polypeptide is detected and/or quantified using any of a number of well recognized immunological binding assays (see, e.g., U.S. Patent Nos. 4,366,241; 4,376,110; 4,517,288; and 4,837,168). For a review of the general immunoassays, see also Asai (1993) Methods in Cell Biology Volume 37: Antibodies in Cell Biology, 5 Academic Press, Inc. New York; Stites & Terr (1991) Basic and Clinical Immunology 7th Edition. In another embodiment, the polypeptide is detected and/or quantified using LuminexTM assay technology. The LuminexTM assay separates tiny color-coded beads into e.g., distinct sets that are each coated with a reagent for a particular bioassay, 10 allowing the capture and detection of specific analytes from a sample in a multiplex manner. The LuminexTM assay technology can be compared to a multiplex ELISA assay using bead-based fluorescence cytometry to detect analytes such as biomarkers. Immunological binding assays (or immunoassays) typically utilize a "capture agent" to specifically bind to and often immobilize the analyte (polypeptide or 15 subsequence). The capture agent is a moiety that specifically binds to the analyte. In another embodiment, the capture agent is an antibody that specifically binds a polypeptide. The antibody (anti-peptide) can be produced by any of a number of means well known to those of skill in the art. Immunoassays also often utilize a labeling agent to specifically bind to and 20 label the binding complex formed by the capture agent and the analyte. The labeling agent can itself be one of the moieties comprising the antibody/analyte complex. Thus, the labeling agent can be a labeled polypeptide or a labeled anti-antibody. Alternatively, the labeling agent can be a third moiety, such as another antibody, that specifically binds to the antibody/polypeptide complex. 25 In one embodiment, the labeling agent is a second human antibody bearing a label. Alternatively, the second antibody can lack a label, but it can, in turn, be bound by a labeled third antibody specific to antibodies of the species from which the second antibody is derived. The second can be modified with a detectable moiety, e.g., as biotin, to which a third labeled molecule can specifically bind, such as enzyme 30 labeled streptavidin. Other proteins capable of specifically binding immunoglobulin constant regions, such as protein A or protein G can also be used as the label agent. These proteins are normal constituents of the cell walls of streptococcal bacteria. They exhibit a strong non-immunogenic reactivity with immunoglobulin constant regions - 69 - 12041-7037WO / 1014 WO from a variety of species (see, generally Kronval, et al. (1973) J. Immunol., 111: 1401-1406, and Akerstrom (1985) J. Immunol., 135: 2589-2542). As indicated above, immunoassays for the detection and/or quantification of a polypeptide can take a wide variety of formats well known to those of skill in the art. 5 Exemplary immunoassays for detecting a polypeptide can be competitive or noncompetitive. Noncompetitive immunoassays are assays in which the amount of captured analyte is directly measured. In one "sandwich" assay, for example, the capture agent (anti-peptide antibodies) can be bound directly to a solid substrate where they are immobilized. These immobilized antibodies then capture polypeptide 10 present in the test sample. The polypeptide thus immobilized is then bound by a labeling agent, such as a second human antibody bearing a label. In competitive assays, the amount of analyte (polypeptide) present in the sample is measured indirectly by measuring the amount of an added (exogenous) analyte (polypeptide) displaced (or competed away) from a capture agent (anti 15 peptide antibody) by the analyte present in the sample. In one competitive assay, a known amount of, in this case, a polypeptide is added to the sample and the sample is then contacted with a capture agent. The amount of polypeptide bound to the antibody is inversely proportional to the concentration of polypeptide present in the sample. In another embodiment, the antibody is immobilized on a solid substrate. The 20 amount of polypeptide bound to the antibody can be determined either by measuring the amount of polypeptide present in a polypeptide/antibody complex, or alternatively by measuring the amount of remaining uncomplexed polypeptide. The amount of polypeptide can be detected by providing a labeled polypeptide. The assays described herein are scored (as positive or negative or quantity of 25 polypeptide) according to standard methods well known to those of skill in the art. The particular method of scoring will depend on the assay format and choice of label. For example, a Western Blot assay can be scored by visualizing the colored product produced by the enzymatic label. A clearly visible colored band or spot at the correct molecular weight is scored as a positive result, while the absence of a clearly visible 30 spot or band is scored as a negative. The intensity of the band or spot can provide a quantitative measure of polypeptide. Antibodies for use in the various immunoassays described herein, can be produced as described herein. - 70 - 12041-7037WO / 1014 WO In vivo techniques for detection of a marker protein include introducing into a subject a labeled antibody directed against the protein. For example, the antibody can be labeled with a radioactive marker whose presence and location in a subject can be detected by standard imaging techniques. 5 Certain markers identified by the methods provided herein can be secreted proteins. It is a simple matter for the skilled artisan to determine whether any particular marker protein is a secreted protein. In order to make this determination, the marker protein is expressed in, for example, a mammalian cell, e.g., a human cell line, extracellular fluid is collected, and the presence or absence of the protein in the 10 extracellular fluid is assessed (e.g., using a labeled antibody which binds specifically with the protein). In other embodiments, biomarker polypeptides can be detected using mass spectrometry (MS). Techniques and instrumentation for detection are known in the art. MS testing can be used to detect protein signatures of response (e.g., in serum). 15 Proteins and Antibody Detection One aspect of the disclosure pertains to isolated proteins which correspond to one or more markers, and biologically active portions thereof. In one embodiment, the native polypeptide corresponding to a marker can be isolated from a biological 20 sample (e.g., a blood sample, a serum sample, a non-cell sample, a cell sample or a tissue sample) by an appropriate purification scheme using standard protein purification techniques. In a preferred embodiment, the proteins are isolated from a serum sample. In another embodiment, the proteins are isolated from a cell-free sample. 25 In another embodiment, polypeptides corresponding to a marker are produced by recombinant DNA techniques. Alternative to recombinant expression, a polypeptide corresponding to a marker provided herein can be synthesized chemically using standard peptide synthesis techniques. An "isolated" or "purified" protein or biologically active portion thereof is 30 substantially free of cellular material or other contaminating proteins from the biological sample, cell or tissue source from which the protein is derived, or substantially free of chemical precursors or other chemicals when chemically synthesized. The language "substantially free of cellular material" includes preparations of protein in which the protein is separated from cellular components of - 71 - 12041-7037WO / 1014 WO the cells from which it is isolated or recombinantly produced. Thus, protein that is substantially free of cellular material includes preparations of protein having less than about 30%, less than about 20%, less than about 10%, or less than about 5% (by dry weight) of heterologous protein (also referred to herein as a "contaminating protein"). 5 When the protein or biologically active portion thereof is recombinantly produced, it can be substantially free of culture medium, i.e., culture medium represents less than about 20%, less than about 10%, or less than about 5% of the volume of the protein preparation. When the protein is produced by chemical synthesis, it can substantially be free of chemical precursors or other chemicals, i.e., it is separated from chemical 10 precursors or other chemicals which are involved in the synthesis of the protein. Accordingly such preparations of the protein have less than about 30%, less than about 20%, less than about 10%, less than about 5% (by dry weight) of chemical precursors or compounds other than the polypeptide of interest. Biologically active portions of a polypeptide corresponding to a marker 15 provided herein include polypeptides comprising amino acid sequences sufficiently identical to or derived from the amino acid sequence of the protein corresponding to the gene products described herein, which include fewer amino acids than the full length protein, and exhibit at least one activity of the corresponding full-length protein. Typically, biologically active portions comprise a domain or motif with at 20 least one activity of the corresponding protein. A biologically active portion of a protein provided herein can be a polypeptide which is, for example, 10, 25, 50, 100 or more amino acids in length. Moreover, other biologically active portions, in which other regions of the protein are deleted, can be prepared by recombinant techniques and evaluated for one or more of the functional activities of the native form of a 25 polypeptide provided herein. In certain embodiments, the polypeptide has an amino acid sequence of a protein encoded by a nucleic acid molecule disclosed herein. Other useful proteins are substantially identical (e.g., at least 60, at least 65, at least 70, at least 75, at least 80, at least 85, at least 86, at least 87, at least 88, at least 89, at least 90, at least 91, at 30 least 92, at least 93, at least 94, at least 95, at least 96, at least 97, at least 98, at least 99, at least 99.5% or greater) to one of these sequences and retain the functional activity of the protein of the corresponding full-length protein yet differ in amino acid sequence. - 72 - 12041-7037WO / 1014 WO An isolated polypeptide corresponding to a marker provided herein, or a fragment thereof, can be used as an immunogen to generate antibodies using standard techniques for polyclonal and monoclonal antibody preparation. The full-length polypeptide or protein can be used or, alternatively, the disclosure provides antigenic 5 peptide fragments for use as immunogens. The antigenic peptide of a protein provided herein comprises at least 8 (or at least 10, at least 15, at least 20, or at least 30 or more) amino acid residues of the amino acid sequence of one of the polypeptides provided herein, and encompasses an epitope of the protein such that an antibody raised against the peptide forms a specific immune complex with a marker 10 provided herein to which the protein corresponds. Exemplary epitopes encompassed by the antigenic peptide are regions that are located on the surface of the protein, e.g., hydrophilic regions. Hydrophobicity sequence analysis, hydrophilicity sequence analysis, or similar analyses can be used to identify hydrophilic regions. An immunogen typically is used to prepare antibodies by immunizing a 15 suitable (i.e., immunocompetent) subject such as a rabbit, goat, mouse, or other mammal or vertebrate. An appropriate immunogenic preparation can contain, for example, recombinantly-expressed or chemically-synthesized polypeptide. The preparation can further include an adjuvant, such as Freund's complete or incomplete adjuvant, or a similar immunostimulatory agent. 20 Accordingly, another aspect of the disclosure pertains to antibodies directed against a polypeptide provided herein. The terms "antibody" and "antibody substance" as used interchangeably herein refer to immunoglobulin molecules and immunologically active portions of immunoglobulin molecules, i.e., molecules that contain an antigen binding site which specifically binds an antigen, such as a 25 polypeptide provided herein. A molecule which specifically binds to a given polypeptide provided herein is a molecule which binds the polypeptide, but does not substantially bind other molecules in a sample, e.g., a biological sample, which naturally contains the polypeptide. Examples of immunologically active portions of immunoglobulin molecules include F(ab) and F(ab') 2 fragments which can be 30 generated by treating the antibody with an enzyme such as pepsin. Also provided herein are polyclonal and monoclonal antibodies. The term "monoclonal antibody" or "monoclonal antibody composition," as used herein, refers to a population of antibody molecules that contain only one species of an antigen binding site capable of immunoreacting with a particular epitope. - 73 - 12041-7037WO / 1014 WO Polyclonal antibodies can be prepared as described above by immunizing a suitable subject with a polypeptide provided herein as an immunogen. Antibody producing cells can be obtained from the subject and used to prepare monoclonal antibodies by standard techniques, such as the hybridoma technique originally 5 described by Kohler and Milstein (1975) Nature 256:495-497, the human B cell hybridoma technique (see Kozbor et al., 1983, Immunol. Today 4:72), the EBV hybridoma technique (see Cole et al., pp. 77-96 In Monoclonal Antibodies and Cancer Therapy, Alan R. Liss, Inc., 1985) or trioma techniques. The technology for producing hybridomas is well known (see generally Current Protocols in 10 Immunology, Coligan et al. ed., John Wiley & Sons, New York, 1994). Hybridoma cells producing a monoclonal antibody provided herein are detected by screening the hybridoma culture supernatants for antibodies that bind the polypeptide of interest, e.g., using a standard ELISA assay. Alternative to preparing monoclonal antibody-secreting hybridomas, a 15 monoclonal antibody can be identified and isolated by screening a recombinant combinatorial immunoglobulin library (e.g., an antibody phage display library) with the polypeptide of interest. Kits for generating and screening phage display libraries are commercially available (e.g., the Pharmacia Recombinant Phage Antibody System, Catalog No. 27-9400-01; and the Stratagene SurJZAP Phage Display Kit, Catalog No. 20 240612). Additionally, examples of methods and reagents particularly amenable for use in generating and screening antibody display library can be found in, for example, U.S. Patent No. 5,223,409; PCT Publication No. WO 92/18619; PCT Publication No. WO 91/17271; PCT Publication No. WO 92/20791; PCT Publication No. WO 92/15679; PCT Publication No. WO 93/01288; PCT Publication No. WO 92/01047; 25 PCT Publication No. WO 92/09690; PCT Publication No. WO 90/02809; Fuchs et al. (1991) Bio/Technology 9:1370-1372; Hay et al. (1992) Hum. Antibod. Hybridomas 3:81-85; Huse et al. (1989) Science 246:1275- 1281; Griffiths et al. (1993) EMBO J. 12:725-734. Additionally, recombinant antibodies, such as chimeric and humanized 30 monoclonal antibodies, comprising both human and non-human portions can be made using standard recombinant DNA techniques. Such chimeric and humanized monoclonal antibodies can be produced by recombinant DNA techniques known in the art, for example using methods described in PCT Publication No. WO 87/0267 1; European Patent Application 184,187; European Patent Application 171,496; - 74 - 12041-7037WO / 1014 WO European Patent Application 173,494; PCT Publication No. WO 86/01533; U.S. Patent No. 4,816,567; European Patent Application 125,023; Better et al. (1988) Science 240:1041-1043; Liu et al. (1987) Proc. Natl. Acad. Sci. USA 84:3439-3443; Liu et al. (1987) J. Immunol. 139:3521- 3526; Sun et al. (1987) Proc. Natl. Acad. Sci. 5 USA 84:214-218; Nishimura et al.(1987) Cancer Res. 47:999-1005; Wood et al. (1985) Nature 314:446-449; and Shaw et al.(1988) J. Natl. Cancer Inst. 80:1553 1559; Morrison (1985) Science 229:1202-1207; Oi et al. (1986) Bio/Techniques 4:214; U.S. Patent 5,225,539; Jones et al. (1986) Nature 321:552-525; Verhoeyan et al. (1988) Science 239:1534; and Beidler et al. (1988) J. Immunol.141:4053-4060. 10 Completely human antibodies can be produced using transgenic mice which are incapable of expressing endogenous immunoglobulin heavy and light chains genes, but which can express human heavy and light chain genes. For an overview of this technology for producing human antibodies, see Lonberg and Huszar (1995) Int. Rev. Immunol. 13:65-93). For a detailed discussion of this technology for producing 15 human antibodies and human monoclonal antibodies and protocols for producing such antibodies, see, e.g., U.S. Patent 5,625,126; U.S. Patent 5,633,425; U.S. Patent 5,569,825; U.S. Patent 5,661,016; and U.S. Patent 5,545,806. In addition, companies such as Abgenix, Inc. (Freemont, CA), can be engaged to provide human antibodies directed against a selected antigen using technology similar to that described above. 20 An antibody directed against a polypeptide corresponding to a marker provided herein (e.g., a monoclonal antibody) can be used to isolate the polypeptide by standard techniques, such as affinity chromatography or immunoprecipitation. Moreover, such an antibody can be used to detect the marker (e.g., in a cellular lysate or cell supernatant) in order to evaluate the level and pattern of expression of the 25 marker. The antibodies can also be used diagnostically to monitor protein levels in tissues or body fluids (e.g., in a tumor cell-containing body fluid) as part of a clinical testing procedure, e.g., to, for example, determine the efficacy of a given treatment regimen. Detection can be facilitated by coupling the antibody to a detectable substance. Examples of detectable substances include, but are not limited to, various 30 enzymes, prosthetic groups, fluorescent materials, luminescent materials, bioluminescent materials, and radioactive materials. Examples of suitable enzymes include, but are not limited to, horseradish peroxidase, alkaline phosphatase, galactosidase, or acetylcholinesterase; examples of suitable prosthetic group - 75 - 12041-7037WO / 1014 WO complexes include, but are not limited to, streptavidin/biotin and avidin/biotin; examples of suitable fluorescent materials include, but are not limited to, umbelliferone, fluorescein, fluorescein isothiocyanate, rhodamine, dichlorotriazinylamine fluorescein, dansyl chloride or phycoerythrin; an example of a 5 luminescent material includes, but is not limited to, luminol; examples of bioluminescent materials include, but are not limited to, luciferase, luciferin, and aequorin, and examples of suitable radioactive materials include, but are not limited 125 131 35 3 to, I, I, S or H. 10 Methods for Detection of Gene Mutations and Gene Expression Methods of evaluating gene, mutations and/or gene products of the biomarkers disclosed herein are well known to those of skill in the art, and are described in WO 2011/060328, incorporated herein by reference. 15 Kits A kit for assessing the responsiveness of a subject having lung cancer to treatment using an HSP90 inhibitor (e.g., in a sample such as a serum sample) is disclosed. The kit can comprise one or more reagents capable of identifying HSP90X, e.g., binding specifically with a nucleic acid or polypeptide corresponding one or 20 more of the biomarkers described herein, e.g., gene products identified herein. Suitable reagents for binding with a polypeptide corresponding to HSP90X include antibodies, antibody derivatives, antibody fragments, and the like. Suitable reagents for binding with a nucleic acid (e.g., a genomic DNA, an mRNA, a spliced mRNA, a cDNA, or the like) include complementary nucleic acids. For example, the nucleic 25 acid reagents can include oligonucleotides (labeled or non-labeled) fixed to a substrate, labeled oligonucleotides not bound with a substrate, pairs of PCR primers, molecular beacon probes, and the like. The present disclosure also encompasses kits for detecting the presence of a polypeptide or nucleic acid corresponding to a marker provided herein in a biological 30 sample, e.g., a sample containing tissue, whole blood, serum, plasma, buccal scrape, saliva, cerebrospinal fluid, urine, stool, and bone marrow. For example, the kit can comprise a labeled compound or agent capable of detecting a polypeptide or an mRNA encoding a polypeptide corresponding to a marker provided herein in a - 76 - 12041-7037WO / 1014 WO biological sample and means for determining the amount of the polypeptide or mRNA in the sample (e.g., an antibody which binds the polypeptide or an oligonucleotide probe which binds to DNA or mRNA encoding the polypeptide). Kits can also include instructions for interpreting the results obtained using the kit. 5 For antibody-based kits, the kit can comprise, for example: (1) a first antibody (e.g., attached to a solid support) which binds to a polypeptide corresponding to a marker provided herein; and, optionally, (2) a second, different antibody which binds to either the polypeptide or the first antibody and is conjugated to a detectable label. For oligonucleotide-based kits, the kit can comprise, for example: (1) an 10 oligonucleotide, e.g., a detectably labeled oligonucleotide, which hybridizes to a nucleic acid sequence encoding a polypeptide corresponding to a marker provided herein or (2) a pair of primers useful for amplifying a nucleic acid molecule corresponding to a marker provided herein. The kit can also comprise, e.g., a buffering agent, a preservative, or a protein stabilizing agent. The kit can further 15 comprise components necessary for detecting the detectable label (e.g., an enzyme or a substrate). The kit can also contain a control sample or a series of control samples which can be assayed and compared to the test sample. Each component of the kit can be enclosed within an individual container and all of the various containers can be within a single package, along with instructions for interpreting the results of the 20 assays performed using the kit. A kit can be any manufacture (e.g., a package or container) comprising at least one reagent, e.g., a probe or an antibody, for specifically detecting a biomarker described herein, the manufacture being promoted, distributed, or sold as a unit for performing the methods described herein. When the compositions, kits, and methods 25 provided herein are used for carrying out the methods provided herein, probes/antibodies to HSP90x can be selected such that a positive result is obtained in at least about 20%, at least about 40%, at least about 60%, at least about 80%, at least about 90%, at least about 95%, at least about 99% or in 100% of subjects afflicted with lung cancer. 30 When a plurality of biomarkers described herein are measured, e.g., are used in the compositions, kits, and methods provided herein, the amount, structure, and/or activity of each marker or level of expression or copy number can be compared with the normal amount, structure, and/or activity of each of the plurality of markers or - 77 - 12041-7037WO / 1014 WO level of expression in samples of the same type obtained from a subject having a cancer, either in a single reaction mixture (i.e., using reagents, such as different fluorescent probes, for each marker) or in individual reaction mixtures corresponding to one or more of the biomarkers described herein, e.g., gene products identified 5 herein. If a plurality of gene products is used, then 1, 2, 3, 4, 5, 6, 7, 8, 9, or more individual markers can be used or identified. Compositions, kits, and methods for assaying serum or plasma in a sample (e.g., a sample obtained from a subject) are disclosed. These compositions, kits, and methods are substantially the same as those described above, except that, where 10 necessary, the compositions, kits, and methods are adapted for use with certain types of samples. For example, when the sample is a serum sample, it can be necessary to adjust the ratio of compounds in the compositions provided herein, in the kits provided herein, or the methods used. Such methods are well known in the art and within the skill of the ordinary artisan. 15 The kit can optionally comprise additional components useful for performing the methods described herein. By way of example, the kit can comprise fluids (e.g., SSC buffer) suitable for annealing complementary nucleic acids or for binding an antibody with a protein with which it specifically binds, one or more sample compartments, an instructional material which describes performance of a method 20 provided herein, a reference sample for comparison of expression levels of the biomarkers described herein, and the like. A kit can comprise a reagent useful for determining protein level or protein activity of a marker. HSP90-Inhibitors, Compositions and Administration 25 HSP90 inhibitors for therapeutic purposes are known in the art. HSP90 inhibiting agents include each member of the family of heat shock proteins having a mass of about 90-kilo Daltons. For example, in humans the highly conserved Hsp90 family includes cytosolic Hsp90a and Hsp90P isoforms, as well as GRP94, which is found in the endoplasmic reticulum, and HSP75/TRAP1, which is found in the 30 mitochondrial matrix. Representative, non-limiting examples include HSP90 inhibitors selected from the group consisting of IPI-493 (Infinity Pharm.), 17-AG, IPI-504 (Infinity Pharm.), 17-AAG (also known as tanespimycin or CNF-1010; BMS), BIIB-021 (also known as CNF-2024, Biogen IDEC), BIIB-028 (Biogen IDEC), AUY-922 (also known as - 78 - 12041-7037WO / 1014 WO VER-49009, Novartis), SNX-5422 (Pfizer), STA-9090, AT-13387 (Astex), XL-888 (Exelixis), MPC-3100 (Myriad), CU-0305 (Curis), 17-DMAG, CNF-1010, a Macbecin (e.g., Macbecin I, Macbecin II), CCT-018159, CCT-129397, PU-H71 (Memorial Sloan Kettering Cancer Center), and PF-04928473 (SNX-2112). Other 5 HSP90 inhibitors are disclosed in Zhang, M-Q. et al., J. Med. Chem 51(18):5494 5497 (2008) and Menzella, H. et al., J. Med. Chem., 52(6):15128-1521 (2009). Additional Hsp90 inhibitors suitable for use include, but are not limited to, ganetespib (also known as STA-9090) (Proia et al., PLoS One. 2011; 6(4):e18552); AUY922 (Brough et al., J. Med. Chem. 2008; 51(2):196-218); DS-2248 (Daiichi Sankyo, 10 ClinicalTrials.gov Identifier: NCT01288430); alvespimycin (also known as 17 DMAG) (Jez et al., Chem. Biol. 2003;10(4):361-8); MPC-3100 (Yu et al., J. Clin. Oncol. 28, 2010 (suppl; abstr. e13112)); AT13387 (Woodhead et al., J. Med. Chem. 2010; 53(16):5956-69); Debio 0932 (also known as CUDC-0305) (Bao et al., Clin. Cancer Res. 2009; 15(12):4046-57); and KW-2478 (Nakashima et al., Clin. Cancer 15 Res. 2010; 16(10):2792-802). The entire contents of the aforesaid publications are incorporated herein by reference. In one embodiment, the HSP90 inhibitor is a free base of a compound provided herein (e.g., a freebase of IPI-504, IPI-493, 17-AG, or 17-AAG). In one embodiment, the HSP90 inhibitor is a pharmaceutically acceptable salt of a compound 20 provided herein (e.g., a pharmaceutically acceptable salt of the freebase of IPI-504, IPI-493, 17-AG, or 17-AAG). 1. IPI-504 Compositions, methods of synthesis, methods of administration, for IPI-504 25 can be found in the art in PCT application W02005/063714, the entire contents of which is incorporated by reference. In one embodiment, provided herein is an HSP90 inhibitor having the following structure, which is also known as IPI-504: - 79 - 12041-7037WO /1014 WO N H X HO N Me e" OH H .OMe MeO Me HO Me O

NH

2 3 wherein X- is chloride. In other embodiments, the present disclosure also provides the isolated analogs of benzoquinone-containing ansamycins, wherein the benzoquinone is 5 reduced to a hydroquinone and trapped as the ammonium salt by reaction of the hydroquinone with a suitable organic or inorganic acid. In one embodiment, the present disclosure provides a pure and isolated compound of formula 1:

R

4 OH X N Ro W N R25 OH R 5 R6

OR

21 R240 R2 R23 R7

P

1 0 R22 Q 0 ,N-R2 7 1 Re 10 or the free base thereof; wherein independently for each occurrence: W is oxygen or sulfur; Q is oxygen, NR, N(acyl) or a bond; X- is a conjugate base of a pharmaceutically acceptable acid; 15 R for each occurrence is independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, heterocycloalkyl, aralkyl, heteroaryl, and heteroaralkyl; - 80 - 12041-7037WO / 1014 WO

R

1 is hydroxyl, alkoxyl, -OC(O)R 8 , -OC(O)OR 9 , -OC(O)NRioR 1 1 , -OS0 2

R

2 ,

-OC(O)NHSO

2

NR

3

R

1 4 , -NR 13

R

14 , or halide; and R 2 is hydrogen, alkyl, or aralkyl; or

R

1 and R 2 taken together, along with the carbon to which they are bonded, represent -(C=O)-, -(C=N-OR)-, -(C=N-NHR)-, or -(C=N-R)-; 5 R 3 and R4 are each independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, aralkyl, heteroaryl, heteroaralkyl, and -[(CR 2 )p]-RI6;or R 3 taken together with R4 represent a 4-8 membered optionally substituted heterocyclic ring;

R

5 is selected from the group consisting of H, alkyl, aralkyl, and a group 10 having the formula la: 0

R

1 7 R17 R17 R17 la wherein R 17 is selected independently from the group consisting of hydrogen, halide, hydroxyl, alkoxyl, aryloxy, acyloxy, amino, alkylamino, arylamino, 15 acylamino, aralkylamino, nitro, acylthio, carboxamide, carboxyl, nitrile, -COR 1 8 , C0 2 Ri 8 , -N(Ri 8 )C0 2

R

19 , -OC(O)N(Ri 8

)(R

19 ), -N(Ri 8 )S0 2

R

19 , -N(Ri 8 )C(O)N(Ri 8

)(R

19 ), and -CH 2 0-heterocyclyl;

R

6 and R 7 are both hydrogen; or R 6 and R 7 taken together form a bond;

R

8 is hydrogen, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, 20 aralkyl, heteroaryl, heteroaralkyl, or -[(CR2)p]-R16;

R

9 is alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, aralkyl, heteroaryl, heteroaralkyl, or -[(CR2)p]-R16; RIO and R 11 are each independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, aralkyl, 25 heteroaryl, heteroaralkyl, and -[(CR 2 )p]-RI 6 ; or Rio and R 11 taken together with the nitrogen to which they are bonded represent a 4-8 membered optionally substituted heterocyclic ring; - 81 - 12041-7037WO / 1014 WO

R

1 2 is alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, aralkyl, heteroaryl, heteroaralkyl, or -[(CR 2 )p]-R 1 6 ;

R

1 3 and R 1 4 are each independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, aralkyl, 5 heteroaryl, heteroaralkyl, and -[(CR 2 )p]-R1 6 ; or R 13 and R 14 taken together with the nitrogen to which they are bonded represent a 4-8 membered optionally substituted heterocyclic ring;

R

)COR

19 , -N(Ri 8

)C(O)OR

1 9 , -N(Ri 8 )S0 2

(R

19 ), 10 -CON(Ri 8

)(R

19 ), -OC(O)N(Ri 8

)(R

19 ), -SO 2 N(Ri 8

)(R

19 ), -N(Ri 8

)(R

19 ), -OC(O)OR 18 ,

-COOR

18 , -C(O)N(OH)(Ri 8 ), -OS(O) 2 0Ri 8 , -S(O) 2 0Ri 8 , -OP(O)(ORi 8

)(OR

1 9 ), -N(Ri 8 )P(O)(ORi 8

)(OR

1 9 ), and -P(O)(ORi 8

)(OR

1 9 ); pis 1,2, 3,4,5,or6;

R

18 for each occurrence is independently selected from the group consisting of 15 hydrogen, alkyl, aryl, cycloalkyl, heterocycloalkyl, aralkyl, heteroaryl, and heteroaralkyl;

R

19 for each occurrence is independently selected from the group consisting of hydrogen, alkyl, aryl, cycloalkyl, heterocycloalkyl, aralkyl, heteroaryl, and heteroaralkyl; or R 18 taken together with R 19 represent a 4-8 membered optionally 20 substituted ring;

R

20 , R 2 1 , R 2 2 , R 2 4 , and R 2 5 , for each occurrence are independently alkyl;

R

2 3 is alkyl, -CH 2 OH, -CHO, -COOR 1 8 , or -CH(ORi 8

)

2 ;

R

2 6 and R27 for each occurrence are independently selected from the group consisting of hydrogen, alkyl, aryl, cycloalkyl, heterocycloalkyl, aralkyl, heteroaryl, 25 and heteroaralkyl; provided that when R 1 is hydroxyl, R 2 is hydrogen, R 6 and R 7 taken together form a double bond, R 2 0 is methyl, R 2 1 is methyl, R 2 2 is methyl, R 2 3 is methyl, R 24 is methyl, R 2 5 is methyl, R 2 6 is hydrogen, R27 is hydrogen, Q is a bond, and W is oxygen; R 3 and R 4 are not both hydrogen nor when taken together represent an 30 unsubstituted azetidine; and - 82 - 12041-7037WO / 1014 WO the absolute stereochemistry at a stereogenic center of formula 1 can be R or S or a mixture thereof and the stereochemistry of a double bond can be E or Z or a mixture thereof. In certain embodiments, the present disclosure relates to the aforementioned 5 compound and the attendant definitions, provided that when R 1 is hydroxyl, R 2 is hydrogen, R 5 is hydrogen, R 6 and R 7 taken together form a double bond, R 2 0 is methyl, R 2 1 is methyl, R 2 2 is methyl, R 2 3 is methyl, R 2 4 is methyl, R 2 5 is methyl, R 26 is hydrogen, R 2 7 is hydrogen, Q is a bond, and W is oxygen; R 3 and R 4 are not both hydrogen nor when taken together represent an unsubstituted azetidine. 10 In certain embodiments, the present disclosure relates to the aforementioned compound and the attendant definitions, wherein R 20 , R 2 1 , R 2 2 , R 2 3 , R 24 , and R 25 are methyl; R 26 is hydrogen, Q is a bond; and W is oxygen. In certain embodiments, the present disclosure relates to the aforementioned compound and the attendant definitions, wherein said pharmaceutically acceptable 15 acid has a pKa between about -10 and about 7 in water. In certain embodiments, the present disclosure relates to the aforementioned compound and the attendant definitions, wherein said pharmaceutically acceptable acid has a pKa between about -10 and about 4 in water. In certain embodiments, the present disclosure relates to the aforementioned 20 compound and the attendant definitions, wherein said pharmaceutically acceptable acid has a pKa between about -10 and about 1 in water. In certain embodiments, the present disclosure relates to the aforementioned compound and the attendant definitions, wherein said pharmaceutically acceptable acid has a pKa between about -10 and about -3 in water. 25 In certain embodiments, the present disclosure relates to the aforementioned compound and the attendant definitions, wherein X- is selected from the group consisting of chloride, bromide, iodide, H 2 PO4-, HS04-, methylsulfonate, benzenesulfonate, p-toluenesulfonate, trifluoromethylsulfonate, 10-camphorsulfonate, naphthalene- 1 -sulfonic acid-5-sulfonate, ethan-1-sulfonic acid-2-sulfonate, cyclamic 30 acid salt, thiocyanic acid salt, naphthalene-2-sulfonate, and oxalate. - 83 - 12041-7037WO / 1014 WO In certain embodiments, the present disclosure relates to the aforementioned compound and the attendant definitions, wherein R 1 is hydroxyl or -OC(O)R 8 . In certain embodiments, the present disclosure relates to the aforementioned compound and the attendant definitions, wherein R 2 is hydrogen. 5 In certain embodiments, the present disclosure relates to the aforementioned compound and the attendant definitions, wherein R 3 and R 4 are independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aralkyl, heteroaralkyl, or -[(CR2)p]-R 1 6 . In certain embodiments, the present disclosure relates to the aforementioned compound and the attendant definitions, wherein R 5 is hydrogen or has a formula la: 0

R

1 7 R 17

R

17 R 17 10 R17 la wherein R 17 is selected independently from the group consisting of hydrogen, halide, hydroxyl, alkoxyl, aryloxy, acyloxy, amino, alkylamino, arylamino, acylamino, aralkylamino, nitro, acylthio, carboxamide, carboxyl, nitrile, -COR 18 , 15 C0 2

R

18 , -N(Ri 8 )C0 2

R

19 , -OC(O)N(Ri 8

)(R

19 ), -N(Ri 8 )S0 2

R

19 , -N(Ri 8 )C(O)N(Ri 8

)(R

19 ), and -CH 2 0-heterocyclyl. In certain embodiments, the present disclosure relates to the aforementioned compound and the attendant definitions, wherein R 6 and R 7 taken together form a double bond. 20 In certain embodiments, the present disclosure relates to the aforementioned compound and the attendant definitions, wherein R 27 is hydrogen. In certain embodiments, the present disclosure relates to the aforementioned compound and the attendant definitions, wherein R 1 is hydroxyl or -OC(O)Rs; and R 2 is hydrogen. 25 In certain embodiments, the present disclosure relates to the aforementioned compound and the attendant definitions, wherein R 1 is hydroxyl or -OC(O)Rs; R 2 is hydrogen; and R 3 and R 4 are independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aralkyl, heteroaralkyl, or -[(CR2)pl-R 16 . - 84 - 12041-7037WO / 1014 WO In certain embodiments, the present disclosure relates to the aforementioned compound and the attendant definitions, wherein R 1 is hydroxyl or -OC(O)Rs; R 2 is hydrogen; R 3 and R 4 are independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aralkyl, heteroaralkyl, or -[(CR 2 )p]-RI 6 ; and R 5 is hydrogen or has a formula la: o

R

1 7 R17 R17 5 R17 la wherein R 17 is selected independently from the group consisting of hydrogen, halide, hydroxyl, alkoxyl, aryloxy, acyloxy, amino, alkylamino, arylamino, acylamino, aralkylamino, nitro, acylthio, carboxamide, carboxyl, nitrile, -COR 18 , 10 C0 2

R

18 , -N(Ri 8 )C0 2

R

19 , -OC(O)N(Ri 8

)(R

19 ), -N(Ri 8 )S0 2

R

19 , -N(Ri 8 )C(O)N(Ri 8

)(R

19 ), and -CH 2 0-heterocyclyl. In certain embodiments, the present disclosure relates to the aforementioned compound and the attendant definitions, wherein R 1 is hydroxyl or -OC(O)Rs; R 2 is hydrogen; R 3 and R 4 are independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, 15 aralkyl, heteroaralkyl, or -[(CR 2 )p]-RI 6 ; R 5 is hydrogen or has a formula la: o

R

17 R17 R17 R17 la wherein R 17 is selected independently from the group consisting of hydrogen, halide, hydroxyl, alkoxyl, aryloxy, acyloxy, amino, alkylamino, arylamino, 20 acylamino, aralkylamino, nitro, acylthio, carboxamide, carboxyl, nitrile, -COR 18 , C0 2

R

18 , -N(Ri 8 )C0 2

R

19 , -OC(O)N(Ri 8

)(R

19 ), -N(Ri 8 )S0 2

R

19 , -N(Ri 8 )C(O)N(Ri 8

)(R

19 ), and -CH 2 0-heterocyclyl; and R 6 and R 7 taken together form a double bond. In certain embodiments, the present disclosure relates to the aforementioned 25 compound and the attendant definitions, wherein R 1 is hydroxyl or -OC(O)Rs; R 2 is - 85 - 12041-7037WO / 1014 WO hydrogen; R 3 and R 4 are independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aralkyl, heteroaralkyl, or -[(CR2)p]-R 1 6 ; R 5 is hydrogen or has a formula la: o

R

17 R 17

R

17 R 17 R17 la 5 wherein R 17 is selected independently from the group consisting of hydrogen, halide, hydroxyl, alkoxyl, aryloxy, acyloxy, amino, alkylamino, arylamino, acylamino, aralkylamino, nitro, acylthio, carboxamide, carboxyl, nitrile, -COR 1 8 , C0 2

R

18 , -N(Ri 8 )C0 2

R

19 , -OC(O)N(Ri 8

)(R

19 ), -N(Ri 8 )S0 2

R

19 , -N(Ri 8 )C(O)N(Ri 8

)(R

19 ), and -CH 2 0-heterocyclyl; R 6 and R 7 taken together form a 10 double bond; and R 2 7 is hydrogen. In certain embodiments, the present disclosure relates to the aforementioned compound and the attendant definitions, wherein R 1 is hydroxyl or -OC(O)Rs; R 2 is hydrogen; R 3 and R 4 are independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aralkyl, heteroaralkyl, or -[(CR2)p]-R 1 6 ; R 5 is hydrogen or has a formula la: o

R

1 7 R17 R17 15 R17 la wherein R 17 is selected independently from the group consisting of hydrogen, halide, hydroxyl, alkoxyl, aryloxy, acyloxy, amino, alkylamino, arylamino, acylamino, aralkylamino, nitro, acylthio, carboxamide, carboxyl, nitrile, -COR 1 8 , 20 C0 2

R

18 , -N(Ri 8 )C0 2

R

19 , -OC(O)N(Ri 8

)(R

19 ), -N(Ri 8 )S0 2

R

19 , -N(Ri 8 )C(O)N(Ri 8

)(R

19 ), and -CH 2 0-heterocyclyl; R 6 and R 7 taken together form a double bond; R 2 7 is hydrogen; and X- is selected from the group consisting of chloride, bromide, iodide, H 2 PO4-, HS04-, methylsulfonate, benzenesulfonate, p toluenesulfonate, trifluoromethylsulfonate, 10-camphorsulfonate, naphthalene-1 25 sulfonic acid-5-sulfonate, ethan-1-sulfonic acid-2-sulfonate, cyclamic acid salt, thiocyanic acid salt, naphthalene-2-sulfonate, and oxalate. - 86 - 12041-7037WO / 1014 WO In certain embodiments, the present disclosure relates to the aforementioned compound and the attendant definitions, wherein R 1 is hydroxyl or -OC(O)Rs; R 2 is hydrogen; R 3 and R 4 are independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aralkyl, heteroaralkyl, or -[(CR 2 )p]-RI 6 ; R 5 is hydrogen or has a formula la: 0

R

17 R17 R17 5 R17 la wherein R 17 is selected independently from the group consisting of hydrogen, halide, hydroxyl, alkoxyl, aryloxy, acyloxy, amino, alkylamino, arylamino, acylamino, aralkylamino, nitro, acylthio, carboxamide, carboxyl, nitrile, -COR 18 , 10 C0 2

R

18 , -N(Ri 8 )C0 2

R

19 , -OC(O)N(Ri 8

)(R

19 ), -N(Ri 8 )S0 2

R

19 , -N(Ri 8 )C(O)N(Ri 8

)(R

19 ), and -CH 2 0-heterocyclyl; R 6 and R 7 taken together form a double bond; R 2 7 is hydrogen; and X- is selected from the group consisting of chloride and bromide. In one embodiment the present disclosure provides a pure and isolated 15 compound with absolute stereochemistry as shown in formula 2:

R

4 OH x 'H e N N Me OH R5

R

6 oOMe MeO H11 Me R7 Me e

HN-R

27 2 or the free base thereof; wherein independently for each occurrence: X- is selected from the group consisting of chloride, bromide, iodide, H 2

PO

4 -, 20 HS04-, methylsulfonate, benzenesulfonate, p-toluenesulfonate, trifluoromethylsulfonate, 10-camphorsulfonate, naphthalene- 1 -sulfonic acid-5 - 87 - 12041-7037WO / 1014 WO sulfonate, ethan-1-sulfonic acid-2-sulfonate, cyclamic acid salt, thiocyanic acid salt, naphthalene-2-sulfonate, and oxalate.

R

1 is hydroxyl or -OC(O)Rs;

R

3 and R4 are hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aralkyl, 5 heteroaralkyl, or -[(CR 2 )p]-RI6;or R 3 taken together with R 4 represent a 4-8 membered optionally substituted heterocyclic ring;

R

5 is hydrogen or has a formula la: 0

R

17 R17 R17 R17 la 10 wherein R 17 is selected independently from the group consisting of hydrogen, halide, hydroxyl, alkoxyl, aryloxy, acyloxy, amino, alkylamino, arylamino, acylamino, aralkylamino, nitro, acylthio, carboxamide, carboxyl, nitrile, -COR 1 8 , C0 2 Ri 8 , -N(Ri 8 )C0 2

R

19 , -OC(O)N(Ri 8

)(R

19 ), -N(Ri 8 )S0 2

R

19 , -N(Ri 8 )C(O)N(Ri 8

)(R

19 ), and -CH 2 0-heterocyclyl; 15 R 6 and R 7 are both hydrogen; or R 6 and R 7 taken together form a bond;

R

8 is hydrogen, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, aralkyl, heteroaryl, heteroaralkyl, or -[(CR2)p]-R 6 ;

R

)COR

19 , -N(Ri 8

)C(O)OR

1 9 , -N(Ri 8 )S0 2

(R

19 ), 20 -CON(Ri 8

)(R

19 ), -OC(O)N(Ri 8

)(R

1 9 ), -SO 2 N(Ri 8

)(R

19 ), -N(Ri 8

)(R

19 ), -OC(O)OR 18 ,

-COOR

18 , -C(O)N(OH)(Ri 8 ), -OS(O) 2 0Ri 8 , -S(O) 2 0Ri 8 , -OP(O)(OR 18

)(OR

19 ), -N(Ri 8 )P(O)(ORi 8

)(OR

19 ), and -P(O)(ORi 8

)(OR

1 9 ); pis 1,2, 3, 4, 5, or6;

R

18 for each occurrence is independently selected from the group consisting of 25 hydrogen, alkyl, aryl, cycloalkyl, heterocycloalkyl, aralkyl, heteroaryl, and heteroaralkyl; - 88 - 12041-7037WO / 1014 WO

R

19 for each occurrence is independently selected from the group consisting of hydrogen, alkyl, aryl, cycloalkyl, heterocycloalkyl, aralkyl, heteroaryl, and heteroaralkyl; or R 18 taken together with R 19 represent a 4-8 membered optionally substituted ring; 5 R 2 7 is hydrogen, alkyl, aryl, cycloalkyl, heterocycloalkyl, aralkyl, heteroaryl, or heteroaralkyl; provided that when R 1 is hydroxyl, R 2 is hydrogen, R 6 and R 7 taken together form a double bond, R 2 7 is hydrogen; R 3 and R 4 are not both hydrogen nor when taken together represent an unsubstituted azetidine; and 10 the stereochemistry of a double bond can be E or Z or a mixture thereof. In certain embodiments, the present disclosure relates to the aforementioned compound and the attendant definitions, provided that when R 1 is hydroxyl, R 5 is hydrogen, R 6 and R 7 taken together form a double bond, R 2 7 is hydrogen; R 3 and R 4 are not both hydrogen nor when taken together represent an unsubstituted azetidine. 15 In certain embodiments, the present disclosure relates to the aforementioned compound and the attendant definitions, wherein R 1 is hydroxyl. In certain embodiments, the present disclosure relates to the aforementioned compound and the attendant definitions, wherein R 3 is allyl. In certain embodiments, the present disclosure relates to the aforementioned 20 compound and the attendant definitions, wherein R 3 has formula 9 Me X, I.H o) 9 or the free base thereof; wherein X1- is selected from the group consisting of chloride, bromide, iodide, 25 H 2 PO4-, HS04-, methylsulfonate, benzenesulfonate, p-toluenesulfonate, trifluoromethylsulfonate, and 10-camphorsulfonate, naphthalene- 1-sulfonic acid-5 sulfonate, ethan-1-sulfonic acid-2-sulfonate, cyclamic acid salt, thiocyanic acid salt, naphthalene-2-sulfonate, and oxalate. - 89 - 12041-7037WO / 1014 WO In certain embodiments, the present disclosure relates to the aforementioned compound and the attendant definitions, wherein R 4 is hydrogen. In certain embodiments, the present disclosure relates to the aforementioned compound and the attendant definitions, wherein R 5 is hydrogen. 5 In certain embodiments, the present disclosure relates to the aforementioned compound and the attendant definitions, wherein R 6 and R 7 taken together form a bond. In certain embodiments, the present disclosure relates to the aforementioned compound and the attendant definitions, wherein R 27 is hydrogen. 10 In certain embodiments, the present disclosure relates to the aforementioned compound and the attendant definitions, wherein R 1 is hydroxyl; R 3 is allyl; and R 4 is hydrogen. In certain embodiments, the present disclosure relates to the aforementioned compound and the attendant definitions, wherein R 1 is hydroxyl; R 3 has formula 9 Me

X

1 15 e 9 or the free base thereof; wherein X1- is selected from the group consisting of chloride, bromide, iodide,

H

2 PO4-, HS04-, methylsulfonate, benzenesulfonate, p-toluenesulfonate, 20 trifluoromethylsulfonate, and 10-camphorsulfonate, naphthalene- 1-sulfonic acid-5 sulfonate, ethan-1-sulfonic acid-2-sulfonate, cyclamic acid salt, thiocyanic acid salt, naphthalene-2-sulfonate, and oxalate; and R 4 is hydrogen. In certain embodiments, the present disclosure relates to the aforementioned compound and the attendant definitions, wherein R 1 is hydroxyl; R 3 is allyl; R 4 is 25 hydrogen; and R 5 is hydrogen. In certain embodiments, the present disclosure relates to the aforementioned compound and the attendant definitions, wherein R 1 is hydroxyl; R 3 has formula 9 - 90 - 12041-7037WO / 1014 WO Me X 1 I H E) M ' 9 or the free base thereof; wherein X1- is selected from the group consisting of chloride, bromide, iodide, 5 H 2 PO4-, HS04-, methylsulfonate, benzenesulfonate, p-toluenesulfonate, trifluoromethylsulfonate, and 10-camphorsulfonate, naphthalene- 1 -sulfonic acid-5 sulfonate, ethan-1-sulfonic acid-2-sulfonate, cyclamic acid salt, thiocyanic acid salt, naphthalene-2-sulfonate, and oxalate; R 4 is hydrogen; and R 5 is hydrogen. In certain embodiments, the present disclosure relates to the aforementioned 10 compound and the attendant definitions, wherein R 1 is hydroxyl; R 3 is allyl; R 4 is hydrogen; R 5 is hydrogen; and R 6 and R 7 taken together form a bond. In certain embodiments, the present disclosure relates to the aforementioned compound and the attendant definitions, wherein R 1 is hydroxyl; R 3 has formula 9 Me X 1 ' 15 9 or the free base thereof; wherein X1- is selected from the group consisting of chloride, bromide, iodide,

H

2 PO4-, HS04-, methylsulfonate, benzenesulfonate, p-toluenesulfonate, trifluoromethylsulfonate, and 10-camphorsulfonate, naphthalene- 1-sulfonic acid-5 20 sulfonate, ethan-1-sulfonic acid-2-sulfonate, cyclamic acid salt, thiocyanic acid salt, naphthalene-2-sulfonate, and oxalate; R 4 is hydrogen; R 5 is hydrogen; and R 6 and R 7 taken together form a bond. In certain embodiments, the present disclosure relates to the aforementioned compound and the attendant definitions, wherein R 1 is hydroxyl; R 3 is allyl; R 4 is 25 hydrogen; R 5 is hydrogen; R 6 and R 7 taken together form a bond; and R 2 7 is hydrogen. In certain embodiments, the present disclosure relates to the aforementioned compound and the attendant definitions, wherein R 1 is hydroxyl; R 3 has formula 9 - 91 - 12041-7037WO / 1014 WO Me X 1 I H E) M ' 9 or the free base thereof; wherein X1- is selected from the group consisting of chloride, bromide, iodide, 5 H 2

PO

4 -, HS04-, methylsulfonate, benzenesulfonate, p-toluenesulfonate, trifluoromethylsulfonate, and 10-camphorsulfonate, naphthalene- 1 -sulfonic acid-5 sulfonate, ethan-1-sulfonic acid-2-sulfonate, cyclamic acid salt, thiocyanic acid salt, naphthalene-2-sulfonate, and oxalate; R 4 is hydrogen; R 5 is hydrogen; R 6 and R 7 taken together form a bond; and R 2 7 is hydrogen. 10 In one embodiment the present disclosure provides a pure and isolated compound with absolute stereochemistry as shown in formula 3: H, ' H OH N Me Me" OH H *OMe MeO Me HO /

NH

2 3 wherein X- is selected from the group consisting of chloride, bromide, iodide,

H

2 PO4-, HS04-, methylsulfonate, benzenesulfonate, p-toluenesulfonate, 15 trifluoromethylsulfonate, and 10-camphorsulfonate, naphthalene- 1-sulfonic acid-5 sulfonate, ethan-1-sulfonic acid-2-sulfonate, cyclamic acid salt, thiocyanic acid salt, naphthalene-2-sulfonate, and oxalate. In certain embodiments, the present disclosure relates to the aforementioned compound and the attendant definitions, wherein X- is chloride. 20 In certain embodiments, the present disclosure relates to the aforementioned compound and the attendant definitions, wherein X- is bromide. In one embodiment, the present disclosure relates to a composition comprising a compound of any one of the aforementioned compounds and an amino acid. - 92 - 12041-7037WO / 1014 WO In certain embodiments, the present disclosure relates to the aforementioned composition and the attendant definitions, wherein the amino acid is selected from the group consisting of: O Me O Me O2 0 H HL~ HO H 2 HO Me HO NH 2 HO 0 0 O HO 2 HO HO NHO' HO O 5 ,, H ,O) , 0 H O N - H O H 2 H O , a n H O - N H , , .and NH 2 In one embodiment the present disclosure provides a compound of formula 4: z [X]n e N R N W OH R 4 R R20

OR

2 1

R

24 0 t 23 R6 R, R22 Q O4 /N-R27 4 R26 or a pharmaceutically acceptable salt thereof; 10 wherein, independently for each occurrence, W is oxygen or sulfur; Z is oxygen or sulfur; Q is oxygen, NR, N(acyl) or a bond; n is equal to 0, 1, or 2; 15 m is equal to 0, 1, or 2; - 93 - 12041-7037WO / 1014 WO X and Y are independently C(R 3 0

)

2 ; wherein R 30 for each occurrence is independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, heterocycloalkyl, aralkyl, heteroaryl, and heteroaralkyl; or -[(CR 2 )p]-R 1 6 ; R for each occurrence is independently selected from the group consisting of 5 hydrogen, alkyl, cycloalkyl, heterocycloalkyl, aralkyl, heteroaryl, and heteroaralkyl;

R

1 is hydroxyl, alkoxyl, -OC(O)R 8 , -OC(O)OR 9 , -OC(O)NRioR 1 1 , -OS0 2

R

2 ,

-OC(O)NHSO

2

NR

3

R

1 4 , N R 1 3

R

14 , or halide; and R 2 is hydrogen, alkyl, or aralkyl; or

R

1 and R 2 taken together, along with the carbon to which they are bonded, represent -(C=O)-, -(C=N-OR)-, -(C=N-NHR)-, or -(C=N-R)-; 10 R 3 are each independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, aralkyl, heteroaryl, heteroaralkyl, and -[(CR 2 )p]-RI 6 ;

R

4 is selected from the group consisting of H, alkyl, aralkyl, and a group having the Formula 4a: 0

R

1 7 R17 R17 15 R17 4a wherein R 17 is selected independently from the group consisting of hydrogen, halide, hydroxyl, alkoxyl, aryloxy, acyloxy, amino, alkylamino, arylamino, acylamino, aralkylamino, nitro, acylthio, carboxamide, carboxyl, nitrile, -COR 1 8 , 20 C0 2 Ri 8 , -N(Ri 8 )C0 2

R

19 , -OC(O)N(Ri 8

)(R

19 ), -N(Ri 8 )S0 2

R

19 , -N(Ri 8 )C(O)N(Ri 8

)(R

19 ), and -CH 2 0-heterocyclyl;

R

5 and R 6 are both hydrogen; or R 5 and R 6 taken together form a bond;

R

8 is hydrogen, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, aralkyl, heteroaryl, heteroaralkyl, or -[(CR2)p]-R16; 25 R 9 is alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, aralkyl, heteroaryl, heteroaralkyl, or -[(CR2)p]-R16; RIO and R 11 are each independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, aralkyl, - 94 - 12041-7037WO / 1014 WO heteroaryl, heteroaralkyl, and -[(CR 2 )p]-RI 6 ; or RIO and R 11 taken together with the nitrogen to which they are bonded represent a 4-8 membered optionally substituted heterocyclic ring;

R

1 3 and R 1 4 are each independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, aralkyl, heteroaryl, heteroaralkyl, and -[(CR 2 )p]-R1 6 ; or R 13 and R 14 taken together with the nitrogen to which they are bonded represent a 4-8 membered optionally substituted 10 heterocyclic ring;

R

)COR

19 , -N(Ri 8

)C(O)OR

1 9 , -N(Ri 8 )S0 2

(R

19 ), -CON(Ri 8

)(R

19 ), -OC(O)N(Ri 8

)(R

19 ), -SO 2

N(RI

8

)(R

19 ), -N(Ri 8

)(R

19 ), -OC(O)ORi 8 ,

-COOR

18 , -C(O)N(OH)(Ri 8 ), -OS(O) 2 ORi 8 , -S(O) 2 ORi 8 , -OP(O)(ORi 8

)(OR

19 ), 15 -N(Ri 8 )P(O)(ORi 8

)(OR

1 9 ), and -P(O)(ORi 8

)(OR

1 9 ); p is 1, 2, 3, 4, 5, or 6;

R

)

2 ;

R

2 6 and R27 for each occurrence are independently selected from the group consisting of hydrogen, alkyl, aryl, cycloalkyl, heterocycloalkyl, aralkyl, heteroaryl, and heteroaralkyl; and the absolute stereochemistry at a stereogenic center of formula 4 can be R or S 30 or a mixture thereof and the stereochemistry of a double bond can be E or Z or a mixture thereof. - 95 - 12041-7037WO / 1014 WO In certain embodiments, the present disclosure relates to the aforementioned compound and the attendant definitions, wherein R 20 , R 2 1 , R 2 2 , R 2 3 , R 24 , R 25 are methyl; R 26 is hydrogen; Q is a bond; and Z and W are oxygen. In certain embodiments, the present disclosure relates to the aforementioned 5 compound and the attendant definitions, wherein R 1 is hydroxyl or -OC(O)R 8 . In certain embodiments, the present disclosure relates to the aforementioned compound and the attendant definitions, wherein R 2 is hydrogen. In certain embodiments, the present disclosure relates to the aforementioned compound and the attendant definitions, wherein R 3 is hydrogen, alkyl, alkenyl, 10 cycloalkyl, aralkyl, heteroaralkyl, or -[(CR2)p]-R 1 6 . In certain embodiments, the present disclosure relates to the aforementioned compound and the attendant definitions, wherein R 4 is hydrogen or has a formula la: 0

R

17 R17 R17

R

17 la 15 wherein R 17 is selected independently from the group consisting of hydrogen, halide, hydroxyl, alkoxyl, aryloxy, acyloxy, amino, alkylamino, arylamino, acylamino, aralkylamino, nitro, acylthio, carboxamide, carboxyl, nitrile, -COR 18 , C0 2

R

18 , -N(Ri 8 )C0 2

R

19 , -OC(O)N(Ri 8

)(R

1 9 ), -N(Ri 8 )S0 2

R

19 , -N(Ris)C(O)N(Ris)(R 1 9 ), and -CH 2 0-heterocyclyl. 20 In certain embodiments, the present disclosure relates to the aforementioned compound and the attendant definitions, wherein R 5 and R 6 taken together form a bond. In certain embodiments, the present disclosure relates to the aforementioned compound and the attendant definitions, wherein X and Y are -CH 2 -. 25 In certain embodiments, the present disclosure relates to the aforementioned compound and the attendant definitions, wherein n is equal to 0; and m is equal to 0 or 1. - 96 - 12041-7037WO / 1014 WO In certain embodiments, the present disclosure relates to the aforementioned compound and the attendant definitions, wherein R 1 is hydroxyl or -OC(O)Rs; and R 2 is hydrogen. In certain embodiments, the present disclosure relates to the aforementioned 5 compound and the attendant definitions, wherein R 1 is hydroxyl or -OC(O)Rs; R 2 is hydrogen; and R 3 is hydrogen, alkyl, alkenyl, cycloalkyl, aralkyl, heteroaralkyl, or -[(CR2)p] -R16. In certain embodiments, the present disclosure relates to the aforementioned compound and the attendant definitions, wherein R 1 is hydroxyl or -OC(O)Rs; R 2 is 10 hydrogen; R 3 is hydrogen, alkyl, alkenyl, cycloalkyl, aralkyl, heteroaralkyl, or -[(CR2)p]-R 6 ; and R 4 is hydrogen or has a formula la: o

R

1 7 R17 R17 R17 la wherein R 17 is selected independently from the group consisting of hydrogen, 15 halide, hydroxyl, alkoxyl, aryloxy, acyloxy, amino, alkylamino, arylamino, acylamino, aralkylamino, nitro, acylthio, carboxamide, carboxyl, nitrile, -COR 18 , C0 2

R

18 , -N(Ri 8 )C0 2

R

19 , -OC(O)N(Ri 8

)(R

19 ), -N(Ri 8 )S0 2

R

19 , -N(Ri 8 )C(O)N(Ri 8

)(R

19 ), and -CH 2 0-heterocyclyl. In certain embodiments, the present disclosure relates to the aforementioned 20 compound and the attendant definitions, wherein R 1 is hydroxyl or -OC(O)Rs; R 2 is hydrogen; R 3 is hydrogen, alkyl, alkenyl, cycloalkyl, aralkyl, heteroaralkyl, or

-[(CR

2 )p]-RI 6 ; R4 is hydrogen or has a formula la: o

R

1 7 R17 R17 R17 la 25 wherein R 17 is selected independently from the group consisting of hydrogen, halide, hydroxyl, alkoxyl, aryloxy, acyloxy, amino, alkylamino, arylamino, - 97 - 12041-7037WO / 1014 WO acylamino, aralkylamino, nitro, acylthio, carboxamide, carboxyl, nitrile, -COR 1 8 , C0 2

R

18 , -N(Ri 8 )C0 2

R

19 , -OC(O)N(Ri 8

)(R

19 ), -N(Ri 8 )S0 2

R

19 , -N(Ri 8 )C(O)N(Ri 8

)(R

19 ), and -CH 2 0-heterocyclyl; and R 5 and R 6 taken together form a bond. 5 In certain embodiments, the present disclosure relates to the aforementioned compound and the attendant definitions, wherein R 1 is hydroxyl or -OC(O)Rs; R 2 is hydrogen; R 3 is hydrogen, alkyl, alkenyl, cycloalkyl, aralkyl, heteroaralkyl, or

-[(CR

2 )p]-RI 6 ; R4 is hydrogen or has a formula la: o

R

1 7 R17 R17 R17 10 la wherein R 17 is selected independently from the group consisting of hydrogen, halide, hydroxyl, alkoxyl, aryloxy, acyloxy, amino, alkylamino, arylamino, acylamino, aralkylamino, nitro, acylthio, carboxamide, carboxyl, nitrile, -COR 18 , C0 2

R

18 , -N(Ri 8 )C0 2

R

19 , -OC(O)N(Ri 8

)(R

19 ), -N(Ri 8 )S0 2

R

19 , 15 -N(Ri 8 )C(O)N(Ri 8

)(R

19 ), and -CH 2 0-heterocyclyl; R 5 and R 6 taken together form a bond; and X and Y are -CH 2 -. In certain embodiments, the present disclosure relates to the aforementioned compound and the attendant definitions, wherein R 1 is hydroxyl or -OC(O)Rs; R 2 is hydrogen; R 3 is hydrogen, alkyl, alkenyl, cycloalkyl, aralkyl, heteroaralkyl, or 20 -[(CR 2 )p]-RI 6 ; R 4 is hydrogen or has a formula la: o

R

1 7 R17 R17 R17 la wherein R 17 is selected independently from the group consisting of hydrogen, halide, hydroxyl, alkoxyl, aryloxy, acyloxy, amino, alkylamino, arylamino, 25 acylamino, aralkylamino, nitro, acylthio, carboxamide, carboxyl, nitrile, -COR 18 , C0 2

R

18 , -N(Ri 8 )C0 2

R

19 , -OC(O)N(Ri 8

)(R

19 ), -N(Ri 8 )S0 2

R

19 , - 98 - 12041-7037WO / 1014 WO -N(Ri 8 )C(O)N(Ri 8

)(R

1 9 ), and -CH 2 0-heterocyclyl; R 5 and R 6 taken together form a bond; X and Y are -CH 2 -; n is equal to 0; and m is equal to 0 or 1. In one embodiment the present disclosure provides a compound with absolute stereochemistry as shown in formula 5: 0 [X], \ RfN O N Me M e "" O H H R 5 %OMe MeO H/,. Me R6

HN-R

27 5 5 wherein independently for each occurrence: n is equal to 0, 1, or 2; m is equal to 0, 1, or 2; X and Y are independently C(R 3 0

)

2 ; wherein R 30 for each occurrence is 10 independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, heterocycloalkyl, aralkyl, heteroaryl, and heteroaralkyl; or -[(CR 2 )p]-R 1 6 ;

R

1 is hydroxyl or -OC(O)Rs;

R

3 is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aralkyl, heteroaralkyl, or -[(CR2)p]-R16; 15 R 5 and R 6 are both hydrogen; or R 5 and R 6 taken together form a bond;

R

8 is hydrogen, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, aralkyl, heteroaryl, heteroaralkyl, or -[(CR2)p]-R16;

R

)COR

19 , -N(Ri 8

)C(O)OR

1 9 , -N(Ri 8 )S0 2

(R

19 ), 20 -CON(Ri 8

)(R

1 9 ), -OC(O)N(Ri 8

)(R

1 9 ), -SO 2 N(Ri 8

)(R

1 9 ), -N(Ri 8

)(R

19 ), -OC(O)OR 18 ,

-COOR

18 , -C(O)N(OH)(Ri 8 ), -OS(O) 2 0Ri 8 , -S(O) 2 0Ri 8 , -OP(O)(ORi 8

)(OR

1 9 ), -N(Ri 8 )P(O)(ORi 8

)(OR

1 9 ), and -P(O)(ORi 8

)(OR

1 9 ); - 99 - 12041-7037WO / 1014 WO pis 1,2, 3, 4, 5, or6;

R

18 for each occurrence is independently selected from the group consisting of hydrogen, alkyl, aryl, cycloalkyl, heterocycloalkyl, aralkyl, heteroaryl, and heteroaralkyl; 5 R 19 for each occurrence is independently selected from the group consisting of hydrogen, alkyl, aryl, cycloalkyl, heterocycloalkyl, aralkyl, heteroaryl, and heteroaralkyl; or R 18 taken together with R 19 represent a 4-8 membered optionally substituted ring;

R

2 7 is hydrogen, alkyl, aryl, cycloalkyl, heterocycloalkyl, aralkyl, heteroaryl, 10 or heteroaralkyl; and the stereochemistry of a double bond can be E or Z or a mixture thereof. In certain embodiments, the present disclosure relates to the aforementioned compound and the attendant definitions, wherein R 1 is hydroxyl. In certain embodiments, the present disclosure relates to the aforementioned 15 compound and the attendant definitions, wherein R 3 is allyl. In certain embodiments, the present disclosure relates to the aforementioned compound and the attendant definitions, wherein R 5 and R 6 taken together form a bond. In certain embodiments, the present disclosure relates to the aforementioned 20 compound and the attendant definitions, wherein R 27 is hydrogen. In certain embodiments, the present disclosure relates to the aforementioned compound and the attendant definitions, wherein X and Y are -CH 2 -. In certain embodiments, the present disclosure relates to the aforementioned compound and the attendant definitions, wherein n is equal to 0; and m is equal to 0 or 25 1. In certain embodiments, the present disclosure relates to the aforementioned compound and the attendant definitions, wherein R 1 is hydroxyl; and R 3 is allyl. In certain embodiments, the present disclosure relates to the aforementioned compound and the attendant definitions, wherein R 1 is hydroxyl; R 3 is allyl; and R 5 30 and R 6 taken together form a bond. - 100 - 12041-7037WO / 1014 WO In certain embodiments, the present disclosure relates to the aforementioned compound and the attendant definitions, wherein R 1 is hydroxyl; R 3 is allyl; R 5 and R 6 taken together form a bond; and R27 is hydrogen. In certain embodiments, the present disclosure relates to the aforementioned 5 compound and the attendant definitions, wherein R 1 is hydroxyl; R 3 is allyl; R 5 and R 6 taken together form a bond; R27 is hydrogen; and X and Y are -CH 2 -. In certain embodiments, the present disclosure relates to the aforementioned compound and the attendant definitions, wherein R 1 is hydroxyl; R 3 is allyl; R 5 and R 6 taken together form a bond; R27 is hydrogen; X and Y are -CH 2 -; n is equal to 0; and 10 m is equal to 0 or 1. In one embodiment the present disclosure provides a compound selected from the group consisting of: 0 0 N N N Me / N Me N N Me" OH H Me"' OH H *'OMe MeO IOMe MeO Me Me HO / HO / M6 O Me O

NH

2 and

NH

2 . The embodiments described above and in the following sections encompass 15 hydroquinone analogs of the geldanamycin family of molecules. In addition to reduced forms of 17-AAG (17-allylamino-18,21-dihydro-17 demethoxygeldanamycin), other compounds of the present disclosure relates to 18,21 dihydro-geldanamycin family including, but not limited to, 18,21-dihydro analogs of 17-Amino-4,5-dihydro-17-demethoxy-geldanamycin; 17-Methylamino-4,5-dihydro 20 17-demethoxygeldanamycin; 17-Cyclopropylamino-4,5-dihydro-17 demethoxygeldanarnycin; 17-(2'-Hydroxyethylamino)-4,5-dihydro-17 demethoxygelclanamycin; 17-(2-Methoxyethylamino)-4,5-dihydro-17 demethoxygeldanamycin; 17-(2'-Fluoroethylamino)-4,5-dihydro-17 demethoxygeldanamycin; 17-(S)-(+)-2-Hydroxypropylamino-4,5-dihydro-17 25 demethoxygeldanamycin; 17-Azetidin-1-yl-4,5-dihydro-17-demethoxygeldanamycin; - 101 - 12041-7037WO / 1014 WO 17-(3-Hydroxyazetidin-1-yl)-4,5-dihydro-17-demethoxygeldanamycin; 17-Azetidin 1-yl-4,5-dihydro-11-alpha-fluoro-17-demethoxygeldanamycin; 17-(2' Cyanoethylamino)-17-demethoxygeldanamycin; 17-(2'-Fluoroethylamino)-17 demethoxygeldanamycin; 17-Amino-22-(2'-methoxyphenacyl)-17 5 demethoxygeldanamycin; 17-Amino-22-(3'-methoxyphenacyl)-17 demethoxygeldanetmycin; 17-Amino-22-(4'-chlorophenacyl)-17 demethoxygeldanamycin; 17-Amino-22-(3',4'-dichlorophenacyl)-17 demethoxygeldanamycin; 17-Amino-22-(4'-amino-3'-iodophenacyl)- 17 demethoxygeldanamycin; 17-Amino-22-(4'-azido-3'-iodophenacyl)-17 10 demethoxygeldanamycin; 17-Amino-11-alpha-fluoro-17-demethoxygeldanamycin; 17-Allylamino-11-alpha-fluoro-17-demethoxygeldanamycin; 17-Propargylamino-11 alpha-fluoro-17-demethoxygeldanamycin; 17-(2'-Fluoroethylamino)-11-alpha-fluoro 17-demethoxygeldanamycin; 17-Azetidin-1-yl-ll-(4'-azidophenyl)sulfamylcarbonyl 17-demethoxygeldanamycin; 17-(2'-Fluoroethylamino)-11-keto-17 15 demethoxygeldanamycin; 17-Azetidin-1-yl-ll-keto-17-demethoxygeldanamycin; and 17-(3'-Hydroxyazetidin-1-yl)-11-keto-17-demethoxygeldanamycin. It will be understood by one skilled in the art that the methodology outlined herein can be used with any amino substituted benzoquinone ansamycin. The compositions can exist as salts of the reduced ansamycin, e.g., HCl or 20 H 2

SO

4 salts. In another embodiment the compounds are co-crystallized with another salt, such as an amino acid, e.g., glycine. In general, in these embodiments, the ratio of amino acid to ansamycin can vary, but is often from 2:1 to 1:2 amino acid:ansamycin. In one embodiment, IPI-504 is formulated as a lyophilized powder. In one 25 embodiment, IPI-504 is supplied in a vial (e.g., about 845 mg of lyophilized drug product per vial), optionally with a second vial containing diluent. In one embodiment, the lyophilized IPI-504 is reconstituted with a diluent to render a reconstituted solution (e.g., about 50 mg/mL). In one embodiment, an appropriate dose of reconstituted IPI-504 is injected into an IV infusion bag (e.g., 250 or 500 mL 30 of 0.9% Sodium Chloride Injection). In one embodiment, the IPI-504 solution is infused over about 30 min, about 40 min, about 50 min, or about 60 min; or between about 30 min and about 60 min. In one embodiment, the administration of the IV dose is completed within four hours of reconstitution. - 102 - 12041-7037WO / 1014 WO In one embodiment, IPI-504 is administered to a subject every 7, 14, or 21, or more, days. In specific embodiments, IPI-504 is administered to a subject every 10, 15, 20, 25, or 30, or more, days. In other embodiments, IPI-504 is administered once, twice, or three times, or more, per week. In other embodiments, IPI-504 is 5 administered in cycles (e.g., once weekly for two weeks, followed by one week of dosing holiday; or once weekly for one, two, three, or four or more weeks, followed by one, two, three, or four or more weeks of dosing holiday). In one embodiment, IPI-504 is administered at a dose of about 100, about 150, about 200, about 225, about 250, about 300, about 350, about 400, about 450, about 500, or about 550 mg/m 2 , or 10 more. In one embodiment, IPI-504 is administered at a dose of about 225, about 300, or about 450 mg/m 2 . In one embodiment, IPI-504 is co-administered with a second agent. In one embodiment, the co-administered second agent is a taxane, such as a docetaxel. In specific embodiment, the docetaxel is administered to a subject every 7, 14, 21, or 28, 15 or more days. In specific embodiments, the docetaxel is administered at a dose of about 30, about 35, about 40, about 45, about 50, about 55, about 60, about 65, about 2 70, or about 75 mg/m , or more. In specific embodiments, IPI-504 is administered once weekly at a dose of about 300 or about 450 mg/m 2 (e.g., days 1, 8, and 15 of a 21-day cycle), in 20 combination with docetaxel administered once every three weeks (e.g., day 1 of a 21 day cycle) at a dose of about 55, about 60, or about 75 mg/m 2 . In specific embodiments, IPI-504 is administered once weekly at a dose of about 300 or about 450 mg/m2 (e.g., days 1, 8, and 15 of a 21-day cycle), in combination with docetaxel administered once weekly (e.g., days 1, 8, and 15 of a 21 25 day cycle) at a dose of about 36 mg/m 2 . In one embodiment, IPI-504 and/or docetaxel is administered once weekly for three weeks in a four-week cycle (one week of dosing holiday). In one embodiment, IPI-504 and/or docetaxel is administered once weekly for six weeks in a eight-week treatment cycle (two weeks of dosing holiday). - 103 - 12041-7037WO / 1014 WO 2. IPI-493 Compositions, methods of synthesis, methods of administration, etc. for IPI 493 can be found in PCT application W02008/073424, the entire contents of which is incorporated by reference. 5 In some embodiments, a pharmaceutical composition for oral administration is provided, comprising a crystallization inhibitor and a compound of formula 1:

R

3 0 R2.N Me e O 4 R Me' 'OMe MeO Me R

HN-R

7 1 or a pharmaceutically acceptable salt thereof; 10 wherein; R'T is H, -OR 8 , -SR 8

-N(R

8 )(R%, -N(R 8

)C(O)R

9 , -N(R 8 )C(O)0R 9 ,

-N(R

8

)C(O)N(R

8 )(R%, -OC(O)R 8 , -OC(O)0R 8 , -OS(O) 2

R

8 , -OS(O) 2 0R 8 ,

-OP(O)

2

OR

8 , CN or a carbonyl moiety; 2 3 each of R2 and R3 independently is H, alkyl, alkenyl, alkynyl, cycloalkyl, 15 cycloalkenyl, heterocycloaklyl, aryl, aralkyl, heteroaryl, heteroaralkyl, -C(=O)CH 3 or 10 2hee3n -[I(C(R ")2)p] -R"; or R2 and R3 taken together with the nitrogen to which they are bonded represent a 3 - 8 membered optionally substituted heterocyclic ring which contains 1-3 heteroatoms selected from 0, N, S, and P; p independently for each occurrence is 0, 1, 2, 3, 4, 5, or 6; 20 R 4 is H, alkyl, alkenyl, or aralkyl; Rad R 6 are each H; or R and R 6 taken together form a bond;

R

7 is hydrogen alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocycloaklyl, aryl, aralkyl, heteroaryl, heteroaralkyl, or-[CR"2pR; each of R2 and R 9 independently for each occurrence is H, alkyl, alkenyl, 25 alkynyl, cycloalkyl, cycloalkenyl, heterocycloaklyl, aryl, aralkyl, heteroaryl, heteroaralkyl, or -[(C(R'")2)p]-R"; or R and R taken together represent a 3-8 membered optionally substituted heterocyclic ring which contains 1-3 heteroatoms - 104 - 12041-7037WO / 1014 WO selected from 0, N, S, and P; R1 0 for each occurrence independently is H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocycloaklyl, aryl, aralkyl, heteroaryl, or heteroaralkyl; and 5 R" for each occurrence independently is H, cycloalkyl, aryl, heteroaryl, heterocyclyl, -OR', -SR', -N(R 8

)(R

9 ), -N(R 8 )C(O)R', -N(R 8 )C(O)OR',

-N(R

8 )C(O)N(R)(R), -OC(O)R', -OC(O)OR', -OS(O) 2 R', -OS(O) 2 OR, -OP(O) 2 0R', -C(O)R', -C(O) 2 R', -C(O)N(R)(R), halide, or CN. In some embodiments R1 is OH, R 4 is H, and R 5 and R6 taken together form a 10 bond. In some embodiments, a pharmaceutical composition for oral administration is provided, comprising a crystallization inhibitor and a compound of formula 1:

R

3 0 N Me M e Me -'OMe MeO Me R 6

HN-R

7 1 15 In certain embodiments, a pharmaceutical composition for oral administration is provided, comprising a crystallization inhibitor and a compound of formula 1:

R

3 0 R2NN Me ,e 0 4 R Me' -'OMe MeO MM O Me R

HN-R

7 1 or a pharmaceutically acceptable salt thereof; 20 wherein; R1 is -OR', -C(=O)CH 3 ,or a carbonyl moiety; - 105 - 12041-7037WO / 1014 WO each of R2 and R3 independently is H, alkyl, alkenyl or -[(C(R ") 2 )p]-R1; or R2 and R 3 taken together with the nitrogen to which they are bonded represent a 3-8 membered optionally substituted heterocyclic ring which contains 1-3 heteroatoms selected from 0, N, S, and P; 5 p independently for each occurrence is 0, 1 or 2;

R

4 is H;

R

5 and R 6 are each H; or R 5 and R 6 taken together form a bond;

R

7 is hydrogen or -[(C(R'")2)p]-R"; each of R8 and R9 independently are H; or R8 and R9 taken together represent a 10 3-8 membered optionally substituted heterocyclic ring which contains 1-3 heteroatoms selected from 0, N, S, and P; R1 0 for each occurrence independently is H; and R" for each occurrence independently is H, -N(R8)(R9) or halide. Examples of benzoquinone ansamycin compounds include those having the 15 following structures: H O H O N O N N O N Me N Me N N ,. O H 0 H 'OMeMeO .'OMeMeO Me Me HO HO M O 0 M O 0

NH

2 NH 2 0 H 0 N N NO NI N Me N NH Me' Me" *'OMe MeO 'OMe MeO Me Me HO /HO / M O6 Me O

NH

2 NH 2 - 106 - 12041-7037WO /1014 WO 0 H O

H

2 N O F . N N Me N Me NN Me'H Me" H .,OMe MeO - *'OMeMeO Me Me HO / HO M6 O Me O

NH

2 NH 2 IO 1 0 N 0 Me O N 1 0 N 0 Me N N ,e . O He H .lOMeMeO . *'OMeMeO Me Me HO HO / Me O4 M6 O

NH

2 NH 2 0 0 H 2 N

H

2 N 0 0 N N H O H O 0, H 0 O O O0

NH

2 ,

NH

2 , - 107 - 12041-7037WO /1014 WO 0

H

2 N o H NN N H N 0 H ,OAc 0 OH ,0 H NH,, NH, H 0 0 N O NN 0 0N II N N H H O OH OOH O

NH

2 , or

NH

2 ,. In one embodiment, the HSP90 inhibitor provided herein is:

H

0 0 0 H 2 N N N H O H Me"H Io 'OMe MeO I OH Me 0 HO O 0 0 0 5 NH 2 or NH 2 , or a pharmaceutically acceptable salt thereof. In some embodiments, compositions provided herein containing amorphous 17-AG resulted in a surprising finding of improved bioavailability relative to crystalline 17-AG even when no crystallization inhibitor was used; such compositions 10 are therefore useful for administration, such as oral administration. In some of the foregoing embodiments, the compound is present in substantially amorphous form. - 108 - 12041-7037WO / 1014 WO Similarly, in some embodiments, the composition contains an amount of crystallization inhibitor of at least about 10%, at least about 25%, at least about 50%, at least about 75% (w/w), based on the total weight of the composition. In some of the foregoing embodiments, the crystallization inhibitor is PVP. In 5 some of the foregoing embodiments, the 17-AG is substantially amorphous. In certain embodiments, the pharmaceutical composition can be in the form of a paste, solution, slurry, ointment, emulsion or dispersion. In certain embodiments, the pharmaceutical composition is, or comprises, a molecular dispersion. In certain embodiments, the crystallization inhibitor can be selected from 10 polyvinylpyrrolidone (PVP) (including homo- and copolymers of polyvinylpyrrolidone and homopolymers or copolymers of N-vinylpyrrolidone); crospovidone; gums; cellulose derivatives (including hydroxypropyl methylcellulose (HPMC), hydroxypropyl methylcellulose phthalate, hydroxypropyl cellulose, ethyl cellulose, hydroxyethylcellulose, sodium carboxymethyl cellulose, calcium 15 carboxymethyl cellulose, sodium carboxymethyl cellulose, and others); dextran; acacia; homo- and copolymers of vinyllactam, and mixtures thereof; cyclodextrins; gelatins; hypromellose phthalate; sugars; polyhydric alcohols; polyethylene glycol (PEG); polyethylene oxides; polyoxyethylene derivatives; polyvinyl alcohol; propylene glycol derivatives and the like, SLS, Tween, Eudragit; and combinations 20 thereof. The crystallization inhibitor can be water soluble or water insoluble. HPMCs vary in the chain length of their cellulosic backbone and consequently in their viscosity as measured for example at a 2% (W/W) in water. HPMC used in the pharmaceutical compositions provided herein can have a viscosity in water (at a concentration of 2 % (w/w)), of about 100 to about 100,000 cP, about 1000 to about 25 15,000 cP, for example about 4000 cP. In certain embodiments, the molecular weight of HPMC used in the pharmaceutical compositions provided herein can have greater than about 10,000, but not greater than about 1,500,000, not greater than about 1,000,000, not greater than about 500,000, or not greater than about 150,000. HPMCs also vary in the relative degree of substitution of available hydroxyl 30 groups on the cellulosic backbone by methoxy and hydroxypropoxy groups. With increasing hydroxypropoxy substitution, the resulting HPMC becomes more hydrophilic in nature. In certain embodiments, the HPMC has about 15% to about 35%, about 19% to about 32%, or about 22% to about 30%, methoxy substitution, and - 109 - 12041-7037WO / 1014 WO having about 3% to about 15%, about 4% to about 12%, or about 7% to about 12%, hydroxypropoxy substitution. HPMCs which can be used in the pharmaceutical compositions are illustratively available under the brand names MethocelTm of Dow Chemical Co. and 5 Metolosem of Shin-Etsu Chemical Co. Examples of suitable HPMCs having medium viscosity include Methocelm E4M, and Methocelm K4M, both of which have a viscosity of about 4000cP at 2 % (w/w) water. Examples of HPMCs having higher viscosity include MethocelTm ElOM, Methocelm K15M, and MethocelTm K100M, which have viscosities of about 10,000 cP, 15,000 cP, and 100,000 cP respectively 10 viscosities at 2 % (w/w) in water. An example of an HPMC is HPMC-acetate succinate, i.e., HPMC-AS. In certain embodiments the PVPs used in pharmaceutical compositions provided herein have a molecular weight of about 2,500 to about 3,000,000 Daltons, about 8,000 to about 1,000,000 Daltons, about 10,000 to about 400,000 Daltons, 15 about 10,000 to about 300,000 Daltons, about 10,000 to about 200,000 Daltons, about 10,000 to about 100,000 Daltons, about 10,000 to about 80,000 Daltons, about 10,000 to about 70,000 Daltons, about 10,000 to about 60,000 Daltons, about 10,000 to about 50,000 Daltons, or about 20,000 to about 50,000 Daltons. In certain instances the PVPs used in pharmaceutical compositions provided herein have a dynamic viscosity, 20 10% in water at 20 'C, of about 1.3 to about 700, about 1.5 to about 300, or about 3.5 to about 8.5 mPas. When PEGs are used they can have an average molecular about 5,000-20,000 Dalton, about 5,000-15,000 Dalton, or about 5,000-10,000 Dalton. Also provided herein is a pharmaceutical composition for oral delivery, 25 comprising 17-AG and at least one pharmaceutically acceptable excipient, wherein said pharmaceutical composition is substantially free of crystalline 17-AG. In certain instances, the 17-AG in such a pharmaceutical composition includes less than about 15 % (w/w), less than about 10 % (w/w), less than about 5 % (w/w), less than about 3 % (w/w), or less than about 1 % (w/w) crystalline17-AG. Such a pharmaceutical 30 composition can be formulated as a solid dosage form (e.g., a tablet or capsule), a paste, emulsion, slurry, or ointment. Also provided herein is a pharmaceutical composition for oral delivery, comprising 17-AAG and at least one pharmaceutically acceptable excipient, wherein said pharmaceutical composition is substantially free of crystalline 17-AAG. In -110- 12041-7037WO / 1014 WO certain instances, the 17-AAG in such a pharmaceutical composition includes less than about 15 % (w/w), less than about 10 % (w/w), less than about 5 % (w/w), less than about 3 % (w/w), or less than about 1 % (w/w) crystalline 17-AAG. Such a pharmaceutical composition can be formulated as a solid dosage form (e.g., a tablet or 5 capsule), a paste, emulsion, slurry, or ointment. As described above, benzoquinone ansamycins and pharmaceutical compositions provided herein can additionally comprise pharmaceutically acceptable carriers and excipients according to conventional pharmaceutical compounding techniques to form a pharmaceutical composition or dosage form. Suitable 10 pharmaceutically acceptable carriers and excipients include, but are not limited to, those described in Remington's, The Science and Practice of Pharmacy, (Gennaro, A. R., ed., 19 h edition, 1995, Mack Pub. Co.), which is herein incorporated by reference. The phrase "pharmaceutically acceptable" refers to additives or compositions that are physiologically tolerable and do not typically produce an allergic or similar untoward 15 reaction, such as gastric upset, dizziness and the like, when administered to an animal, such as a mammal (e.g., a human). For oral liquid pharmaceutical compositions, pharmaceutical carriers and excipients can include, but are not limited to water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents, and the like. Oral solid pharmaceutical compositions can include, but are not limited to starches, 20 sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders and disintegrating agents. The pharmaceutical composition and dosage form can also include a benzoquinone ansamycin compound or solid form thereof as discussed above. The solid forms described herein can be useful for making pharmaceutical 25 compositions suitable for oral administration. Such pharmaceutical compositions can contain any of the benzoquinone ansamycin compounds described herein, for example, in an amorphous form and no crystallization inhibitor, or an amorphous form in combination with a crystallization inhibitor. Examples of such benzoquinone ansamycins are described in Schnur et al., J. Med. Chem. 1995, 38: 3 806-12. 30 In one embodiment, provided herein is a pharmaceutical composition comprising an HSP90 inhibitor provided herein, e.g., a pharmaceutical composition comprising IPI-504, IPI-493, or 17-AAG, or a pharmaceutically acceptable salt or free base thereof. See, e.g., W02008073424, W02005063714, US20120052120, -111 - 12041-7037WO / 1014 WO US20120100218, US20110076308, the contents of all of which are incorporated herein by reference. Therapeutic Methods 5 Alternatively, or in combination with the methods described herein, provided herein is a method of treating a cancer, e.g., a lung cancer, with one or more HSP90 inhibitors, alone or in combination, e.g., in combination with a chemotherapeutic agent, such as a taxane. In one embodiment, the method comprises administering to the subject an HSP inhibitor, e.g., one or more HSP90 inhibitors as described herein, 10 alone or in combination with a taxane, in an amount sufficient to reduce or inhibit the cancer cell growth, and/or treat or prevent one or more cancers, in the subject. "Treat," "treatment," and other forms of this word refer to the administration of an HSP90 inhibiting agent, alone or in combination with a second agent to impede growth of a cancer, to cause a cancer to shrink by weight or volume, to extend the 15 expected survival time of the subject and or time to progression of the tumor or the like. In those subjects, treatment can include, but is not limited to, inhibiting tumor growth, reducing tumor mass, reducing size or number of metastatic lesions, inhibiting the development of new metastatic lesions, prolonged survival, prolonged progression-free survival, prolonged time to progression, and/or enhanced quality of 20 life. As used herein, unless otherwise specified, the terms "prevent," "preventing" and "prevention" contemplate an action that occurs before a subject begins to suffer from the regrowth of the cancer and/or which inhibits or reduces the severity of the cancer. 25 As used herein, and unless otherwise specified, the terms "manage," "managing" and "management" encompass preventing the recurrence of the cancer in a patient who has already suffered from the cancer, and/or lengthening the time that a patient who has suffered from the cancer remains in remission. The terms encompass modulating the threshold, development and/or duration of the cancer, or changing the 30 way that a patient responds to the cancer. As used herein, and unless otherwise specified, a "therapeutically effective amount" of a compound is an amount sufficient to provide a therapeutic benefit in the treatment or management of the cancer, or to delay or minimize one or more symptoms associated with the cancer. A therapeutically effective amount of a - 112 - 12041-7037WO / 1014 WO compound means an amount of therapeutic agent, alone or in combination with other therapeutic agents, which provides a therapeutic benefit in the treatment or management of the cancer. The term "therapeutically effective amount" can encompass an amount that improves overall therapy, reduces or avoids symptoms or 5 causes of the cancer, or enhances the therapeutic efficacy of another therapeutic agent. As used herein, and unless otherwise specified, a "prophylactically effective amount" of a compound is an amount sufficient to prevent regrowth of the cancer, or one or more symptoms associated with the cancer, or prevent its recurrence. A prophylactically effective amount of a compound means an amount of the compound, 10 alone or in combination with other therapeutic agents, which provides a prophylactic benefit in the prevention of the cancer. The term "prophylactically effective amount" can encompass an amount that improves overall prophylaxis or enhances the prophylactic efficacy of another prophylactic agent. As used herein, the term "patient" or "subject" refers to an animal, typically a 15 human (i.e., a male or female of any age group, e.g., a pediatric patient (e.g., infant, child, adolescent) or adult patient (e.g., young adult, middle-aged adult or senior adult) or other mammal, such as a primate (e.g., cynomolgus monkey, rhesus monkey); commercially relevant mammals such as cattle, pigs, horses, sheep, goats, cats, and/or dogs; and/or birds, including commercially relevant birds such as 20 chickens, ducks, geese, and/or turkeys, that will be or has been the object of treatment, observation, and/or experiment. When the term is used in conjunction with administration of a compound or drug, then the patient has been the object of treatment, observation, and/or administration of the compound or drug. In some embodiments, the HSP90 inhibitor is a first line treatment for the 25 cancer, i.e., it is used in a patient who has not been previously administered another drug intended to treat the cancer. In other embodiments, the HSP90 inhibitor is a second line treatment for the cancer, i.e., it is used in a patient who has been previously administered another drug intended to treat the cancer. 30 In other embodiments, the HSP90 inhibitor is a third or fourth line treatment for the cancer, i.e., it is used in a patient who has been previously administered two or three other drugs intended to treat the cancer. - 113 - 12041-7037WO / 1014 WO In some embodiments, the HSP90 inhibitor is administered to a patient following surgical excision/removal of the cancer. In some embodiments, the HSP90 inhibitor is administered to a patient before, during, and/or after radiation treatment of the cancer. 5 In one embodiment, the cancer evaluated and/or treated has one or more alterations in: an ALK gene or gene product, e.g., an ALK rearrangement; or a MAPK pathway (e.g., K-Ras) gene or gene product. MAPK pathway activation has been detected in a wide variety of cancers. For example, Ras and Raf mutations have been detected in cancers including, but not limited to: 10 (i) lung cancer (B-raf and K-Ras mutations in NSCLC: Brose et al., Cancer Res. (2002) 62:6997-7000; C-Raf mutations in NSCLC: Kerkhoff et al., Cell Growth Differ.(2000) 11:185-190; C-Raf mutations in SCLC: Graziano et al., Chromosomes Cancer (1991) 3:283-293; K-Ras mutations: Rodenhuis et al., Cancer Res.(1988) 48:5738-5741); 15 (ii) pancreatic cancer (C-Raf mutations: Berger et al., J. Surg. Res. (1997) 69:199-204; K-Ras mutations: Almoquera et al., Cell (1988) 53:549-554, Smith et al., Nucleic Acids Res. (1988) 16:7773-7782, Grunewald et al., Int. J. Cancer (1989) 43:1037-1041, Laghi et al., Oncogene (2002 21:4301-4306); 20 (iii) salivary gland cancer (H-Ras mutations: Yoo et al.,Arch. Pathol. Lab. Med. (2000) 124:836-839); or (iv) skin cancer (B-raf mutations in melanoma: Davies et al., Nature (2002) 417:949-954; Pollock et al., Cancer Cell (2002) 2:5-7; B-raf and K-ras mutations in melanoma: Brose et al., Cancer Res. (2002) 62:6997-7000; 25 H-Ras mutations in keratoacanthoma: Leon et al., Mol. Cell. Biol. (1988) 8:786-793; N-Ras mutations in melanoma: Van't Veer et al., Mol. Cell. Biol. (1989) 9:3114-3116). In certain embodiments, the cancer or tumor identified or treated by the methods provided herein includes, but is not limited to, a solid tumor, a soft tissue 30 tumor, and a metastatic lesion (e.g., a cancer as described herein). In some embodiments, the cancer identified or treated harbors one or more alterations in a gene or gene product chosen from one or more of ALK, RAS (e.g., one or more of H Ras, N-Ras, or K-Ras), EGFR, PIK3CA, RAF (e.g., one or more of A-Raf, B-Raf (BRAF) or C-Raf), PTEN, AKT, TP53 (p53), CTNNB1 (beta-catenin), APC, KIT, - 114 - 12041-7037WO / 1014 WO JAK2, NOTCH, FLT3, MEK, ERK, RSK, ETS, ELK-1, SAP-1, CDKN2a, KEAP1, NFE2L2, HLA-A, p13K, ErbB-2, CDK, DDR2, PDGFR, FGFR, retinoblastoma 1, or cullin 3. In certain embodiments, the cancer is chosen from one or more of lung cancer 5 (e.g., small cell lung cancer, non-small cell lung cancer, squamous cell carcinoma of the lung, adenocarcinoma of the lung, bronchogenic carcinoma), pancreatic cancer, salivary cancer, or skin cancer (e.g., melanoma). In certain embodiments, the cancer is lung cancer. In certain embodiments, the lung cancer is small cell lung cancer (SCLC). In certain embodiments, the lung 10 cancer is non-small cell lung cancer (NSCLC). Non-small cell lung cancer (NSCLC) is a heterogeneous disease that can be sub-classified based on "driver mutations," in which specific oncogene mutations result in dependence upon the driver's signaling pathway, or "oncogene addiction." Common driver mutations in NSCLC appear to involve the genes for K-Ras, epidermal growth factor receptor (EGFR), and anaplastic 15 lymphoma kinase (ALK) (Suda K. et al. (2010) Cancer Metastasis Rev. 29(i):49-60; Sharma S. V. et al. (2007) Nat Rev Cancer.7(3):169-181; Shaw A. T. et al. (2009) 27(26):4247-4253). When potent and specific inhibitors are used to block the signal from the driver oncogene, treatment can be effective, as demonstrated in the case of EGFR tyrosine kinase inhibitors (TKIs) in EGFR-mutant NSCLC (Mok T. S. et al. 20 (2009) N. Engl. J. Med. 361(10):947-957; Kobayashi K. et al. (2009) J. Clin. Oncol. 27(15s):suppl abstr. 8016; Mitsudomi T. et al. (2010) Lancet Oncol.11(2):121-128). This success can be mirrored with ALK TKI therapy in ALK-rearranged NSCLC (Kwak E. L. et al. (2009) J Clin Oncol. 27(15s):suppl; abstr 3509). As of 2009, non small cell lung cancer accounts for approximately 85% of all lung cancers. 25 Approximately 262,000 stage IIIB/IV are diagnosed every year. In 2009, the % of NSCLC patients is distributed as follows: approx. 18% patients have large cell carcinoma, 47% of the patients have adenocarcinoma, and 35% of the patients have squamous cell carcinoma. With respect to the smoking status, approx. 70% of the patient are smokers with greater that 15 pack-years, 13% of the patients have less or 30 equal to 15 pack-years; 15% of the patients are non-smokers; and 2% of the patients have a history of second hand smoking. The disclosure also relates to methods of extending relapse free survival in a cancer patient who is undergoing or has undergone cancer therapy (for example, treatment with a chemotherapeutic (including small molecules and biotherapeutics, - 115 - 12041-7037WO / 1014 WO e.g., antibodies), radiation therapy, surgery, RNAi therapy and/or antisense therapy) by administering a therapeutically effective amount of a HSP90 inhibitor to the patient. "Relapse free survival", as understood by those skilled in the art, is the length of time following a specific point of cancer treatment during which there is no 5 clinically-defined relapse in the cancer. In some embodiments, the HSP90 inhibitor is administered concurrently with the cancer therapy. In instances of concurrent administration, the HSP90 inhibitor can continue to be administered after the cancer therapy has ceased. In other embodiments, the HSP90 inhibitor is administered after cancer therapy has ceased (i.e., with no period of overlap with the cancer treatment). 10 The HSP90 inhibitor can be administered immediately after cancer therapy has ceased, or there can be a gap in time (e.g., up to about a day, a week, a month, six months, or a year) between the end of cancer therapy and the administration of the HSP90 inhibitor. Treatment with the HSP90 inhibitor can continue for as long as relapse-free survival is maintained (e.g., up to about a day, a week, a month, six 15 months, a year, two years, three years, four years, five years, or longer). In one aspect, provided herein is a method of extending relapse free survival in a cancer patient who had previously undergone cancer therapy (for example, treatment with a chemotherapeutic (including small molecules and biotherapeutics, e.g., antibodies), radiation therapy, surgery, RNAi therapy and/or antisense therapy) 20 by administering a therapeutically effective amount of a HSP90 inhibitor to the patient after the cancer therapy has ceased. The HSP90 inhibitor can be administered immediately after cancer therapy has ceased, or there can be a gap in time (e.g., up to about a day, a week, a month, six months, or a year) between the end of cancer therapy and the administration of the HSP90 inhibitor. 25 Combination Therapy It will be appreciated that the HSP90 inhibitor, as described above and herein, can be administered in combination with one or more additional therapies, e.g., such as radiation therapy, surgery and/or in combination with one or more therapeutic 30 agents,to treat the cancers described herein. In one embodiment, the HSP90 inhibitor is administered in combination with a taxane. By "in combination with," it is not intended to imply that the therapy or the therapeutic agents must be administered at the same time and/or formulated for delivery together, although these methods of delivery are within the scope of the - 116 - 12041-7037WO / 1014 WO disclosure. The pharmaceutical compositions can be administered concurrently with, prior to, or subsequent to, one or more other additional therapies or therapeutic agents. In general, each agent will be administered at a dose and/or on a time schedule determined for that agent. In will further be appreciated that the additional 5 therapeutic agent utilized in this combination can be administered together in a single composition or administered separately in different compositions. The particular combination to employ in a regimen will take into account compatibility of the inventive pharmaceutical composition with the additional therapeutically active agent and/or the desired therapeutic effect to be achieved. 10 In general, it is expected that additional therapeutic agents utilized in combination be utilized at levels that do not exceed the levels at which they are utilized individually. In some embodiments, the levels utilized in combination will be lower than those utilized individually. In certain embodiments, the cancer treated by the methods described herein 15 can be selected from, for example, paclitaxel or a paclitaxel agent; or docetaxel. In some embodiments, the HSP90 inhibitor is administered in combination with paclitaxel or a paclitaxel agent, e.g., TAXOL@, protein-bound paclitaxel (e.g., ABRAXANE@). A "paclitaxel agent" as used herein refers to a formulation of paclitaxel (e.g., for example, TAXOL@) or a paclitaxel equivalent (e.g., for example, 20 a prodrug of paclitaxel). Exemplary paclitaxel equivalents include, but are not limited to, nanoparticle albumin-bound paclitaxel (ABRAXANE@, marketed by Abraxis Bioscience), docosahexaenoic acid bound-paclitaxel (DHA-paclitaxel, Taxoprexin, marketed by Protarga), polyglutamate bound-paclitaxel (PG-paclitaxel, paclitaxel poliglumex, CT-2103, XYOTAX@, marketed by Cell Therapeutic), the tumor 25 activated prodrug (TAP), ANG105 (Angiopep-2 bound to three molecules of paclitaxel, marketed by ImmunoGen), paclitaxel-EC-1 (paclitaxel bound to the erbB2 recognizing peptide EC-1; see Li et al., Biopolymers (2007) 87:225-230), and glucose-conjugated paclitaxel (e.g., 2'-paclitaxel methyl 2-glucopyranosyl succinate, see Liu et al., Bioorganic & Medicinal ChemistryLetters (2007) 17:617-620). In 30 certain embodiments, the paclitaxel agent is a paclitaxel equivalent. In certain embodiments, the paclitaxel equivalent is ABRAXANE@. Additional examples of suitable therapeutics for use in combination with the HSP90 inhibitors for treatment of non-small cell lung cancer includes, but are not limited to, a chemotherapeutic agent, e.g., vinorelbine, cisplatin, docetaxel, - 117 - 12041-7037WO / 1014 WO pemetrexed disodium, etoposide, gemcitabine, carboplatin, liposomal SN-38, TLK286, temozolomide, topotecan, pemetrexed disodium, azacitidine, irinotecan, tegafur-gimeracil-oteracil potassium, sapacitabine); tyrosine kinase inhibitor (e.g., EGFR inhibitor (e.g., erlotinib, gefitinib, cetuximab, panitumumab, necitumumab, PF 5 00299804, nimotuzumab, R05083945), MET inhibitor (e.g., PF-02341066, ARQ 197), P13K kinase inhibitor (e.g., XL147, GDC-0941), Raf/MEK dual kinase inhibitor (e.g., R05126766), PI3K/mTOR dual kinase inhibitor (e.g., XL765), SRC inhibitor (e.g., dasatinib), dual inhibitor (e.g., BIBW 2992, GSK1363089, ZD6474, AZD0530, AG-013736, lapatinib, MEHD7945A, linifanib), multikinase inhibitor (e.g., sorafenib, 10 sunitinib, pazopanib, AMG 706, XL184, MGCD265, BMS-690514, R935788), VEGF inhibitor (e.g., endostar, endostatin, bevacizumab, cediranib, BIBF 1120, axitinib, tivozanib, AZD2171), cancer vaccine (e.g., BLP25 liposome vaccine , GVAX, recombinant DNA and adenovirus expressing L523S protein), Bcl-2 inhibitor (e.g., oblimersen sodium), proteasome inhibitor (e.g., bortezomib, carfilzomib, NPI-0052, 15 MLN9708), paclitaxel or a paclitaxel agent, docetaxel, IGF-1 receptor inhibitor (e.g., cixutumumab, MK-0646, OSI 906, CP-751,871, B11B022), hydroxychloroquine, HSP90 inhibitor (e.g., IPI-493, IPI-504, tanespimycin, STA-9090, AUY922, XL888), mTOR inhibitor (e.g., everolimus, temsirolimus, ridaforolimus), Ep-CAM-/CD3 bispecific antibody (e.g., MT110), CK-2 inhibitor (e.g., CX-4945), HDAC inhibitor 20 (e.g., MS 275, LBH589, vorinostat, valproic acid, FR901228), DHFR inhibitor (e.g., pralatrexate), retinoid (e.g., bexarotene, tretinoin), antibody-drug conjugate (e.g., SGN-15), bisphosphonate (e.g., zoledronic acid), cancer vaccine (e.g., belagenpumatucel-L), low molecular weight heparin (LMWH) (e.g., tinzaparin, enoxaparin), GSK1572932A, melatonin, talactoferrin, dimesna, topoisomerase 25 inhibitor (e.g., amrubicin, etoposide, karenitecin), nelfinavir, cilengitide, ErbB3 inhibitor (e.g., MM-121, U3-1287), survivin inhibitor (e.g., YM155, LY2181308), eribulin mesylate, COX-2 inhibitor (e.g., celecoxib), pegfilgrastim, Polo-like kinase 1 inhibitor (e.g., BI 6727), TRAIL receptor 2 (TR-2) agonist (e.g., CS-1008), CNGRC peptide-TNF alpha conjugate, dichloroacetate (DCA), HGF inhibitor (e.g., SCH 30 900105), SAR240550, PPAR-gamma agonist (e.g., CS-7017), gamma-secretase inhibitor (e.g., R04929097), epigenetic therapy (e.g., 5-azacitidine), nitroglycerin, MEK inhibitor (e.g., AZD6244), cyclin-dependent kinase inhibitor (e.g., UCN-01), cholesterol-Fus1, antitubulin agent (e.g., E7389), famesyl-OH-transferase inhibitor (e.g., lonafarnib), immunotoxin (e.g., BB-10901, SS1 (dsFv) PE38), fondaparinux, - 118 - 12041-7037WO / 1014 WO vascular-disrupting agent (e.g., AVE8062), PD-L1 inhibitor (e.g., MDX-1105, MDX 1106), beta-glucan, NGR-hTNF, EMD 521873, MEK inhibitor (e.g., GSK1 120212), epothilone analog (e.g., ixabepilone), kinesin-spindle inhibitor (e.g., 4SC-205), telomere targeting agent (e.g., KML-001), P70 pathway inhibitor (e.g., LY2584702), 5 AKT inhibitor (e.g., MK-2206), angiogenesis inhibitor (e.g., lenalidomide), Notch signaling inhibitor (e.g., OMP-21M18), radiation therapy, surgery, and combinations thereof. Additional examples of suitable therapeutics for use in combination with the HSP90 inhibitors for treatment of small cell lung cancer include, but are not limited 10 to, a chemotherapeutic agent, e.g., etoposide, carboplatin, cisplatin, irinotecan, topotecan, gemcitabine, liposomal SN-38, bendamustine, temozolomide, belotecan, NK012, FR901228, flavopiridol); tyrosine kinase inhibitor (e.g., EGFR inhibitor (e.g., erlotinib, gefitinib, cetuximab, panitumumab); multikinase inhibitor (e.g., sorafenib, sunitinib); VEGF inhibitor (e.g., bevacizumab, vandetanib); cancer vaccine (e.g., 15 GVAX); Bcl-2 inhibitor (e.g., oblimersen sodium, ABT-263); proteasome inhibitor (e.g., bortezomib (Velcade), NPI-0052); IGF-1 receptor inhibitor (e.g., AMG 479); HGF/SF inhibitor (e.g., AMG 102, MK-0646); chloroquine; Aurora kinase inhibitor (e.g., MLN8237); radioimmunotherapy (e.g., TF2); HSP90 inhibitor (e.g., IPI-493, IPI-504, tanespimycin, STA-9090); mTOR inhibitor (e.g., everolimus); Ep-CAM 20 /CD3-bispecific antibody (e.g., MT110); CK-2 inhibitor (e.g., CX-4945); HDAC inhibitor (e.g., belinostat); SMO antagonist (e.g., BMS 833923); peptide cancer vaccine, and radiation therapy (e.g., intensity-modulated radiation therapy (JMRT), hypofractionated radiotherapy, hypoxia-guided radiotherapy), surgery, and combinations thereof. 25 This disclosure is further illustrated by the following examples which should not be construed as limiting. The contents of all references, figures, sequence listing, patents and published patent applications cited throughout this application are hereby incorporated by reference. 30 - 119 - 12041-7037WO / 1014 WO EXEMPLIFICATION This disclosure is further illustrated by the following examples which should not be construed as limiting. The contents of all references, figures, sequence listing, patents and published patent applications cited throughout this application are hereby 5 incorporated by reference. Example 1: Preparation of the hydrochloride salt of the hydroquinone of 17 AAG H 0CI ONH ,H OH e Me D O ND I M' H I1. 10% Na 2

S

2

O

4 (aq) N Me Me O0H H | .OMeMeO 2. HCI Me"' Me -OMe MeO HO / Me M0 HO D NH2 Me 04 2 NH 2 10 17-AAG (0.450 g, 0.768 mmol, 1.0 equiv.) was dissolved in dichloromethane (50 mL) and stirred with a 10% aqueous solution of sodium hydrosulfite (50 mL). The solution was stirred for 30 minutes. The organic layer was collected, dried over Na 2

SO

4 , filtered and transferred to a round bottom flask. To this solution was added a solution of HCl in dioxane (4 N, 0.211 mL, 1.1 equiv.). The resulting mixture was 15 allowed to stir under nitrogen for 30 minutes. A yellow solid slowly crashed out of solution. The yellow solid was purified by recrystallization from MeOH/EtOAc to yield 0.386 g of the hydroquinone HCl salt (2). Compound 2 is also referred to herein as "IPI-504." IPI-504 (retaspimycin hydrochloride) is a water-soluble, potent inhibitor of HSP90x. 20 Additional salts of 17-AAG can be prepared following the procedures described herein, and/or known in the art (see e.g., US 2006/0019941, US 7,375,217 and US 7,767,663, the contents of which are hereby incorporated by reference). For example, US 2006/0019941 discloses hydrobromide salts, p-toluenesulfonate salts, d camphorsulfonate salts, hydrogen phosphate salts, methylsulfonate salts, 25 benzenesulfonate salts, of 17-AAG. US 7,767,663 discloses the preparation of salts of 17-AAG, including dimethylamino acetate co-salts (disclosed in Example 3 of US 7,767,663), a-aminoisobutyrate co-salts (Example 4), -alanine co-salts (Example 5), N-methyl glycine co-salts (Example 6), piperidine carboxylate co-salts (Example 7), - 120 - 12041-7037WO / 1014 WO glycine co-salts (Example 8), 2-amino-2-ethyl-butyrate co-salts (Example 9), 1 amino-cyclopropanecarboxylate co-salts (Example 10), 1-amino cyclopentanecarboxylate co-salts (Example 12), N-methyl piperidinecarboxylate co salts (Example 13), N,N,N-trimethylammonium acetate co-salts (Example 14). 5 The preparation of exemplary solid and liquid formulations of IPI-504 is disclosed in Examples 32-35 of US 2006/0019941. Example 2: High levels of HSP90aare predictive of responsiveness to treatment with IPI-504 in combination with docetaxel 10 This example describes the relationship between the level of circulating HSP90x and responsiveness to IPI-504, administered as a monotherapy, or as a combined treatment of docetaxel and IPI-504, to patients with NSCLC. Absolute levels of HSP90x reported in the Examples herein are exemplary values calculated based on particular subject samples. It shall be understood that 15 these values are presented as examples and are not limiting. Absolute levels can vary depending on, e.g., the sample of patients, assay conditions, sample conditions (e.g., extent of hemolysis), and/or individual characteristics of the patients studied (e.g., tumor histology (e.g., squamous cell carcinoma versus adenocarcinoma), KRAS mutant status, and/or history of smoking). 20 Criteria and administration details for patients undergoing IPI-504 monotherapy are described in NIH Clinical Trial NCT00431015 (also referred to herein as "IPI-504-03"). In essence, patients with pathologically confirmed diagnosis of Stage IIlb (with malignant pleural or pericardial effusion) or Stage IV NSCLC were selected. A typical doses used was 225 mg/m2 where IPI-504 was administered 25 on a twice weekly without a break schedule. Criteria and administration details for patients undergoing IPI-504 in combination with docetaxel are described in NIH Clinical Trial NCT00606814 (also referred to herein as "IPI-504-05"). In essence, patients with pretreated metastatic NSCLC and no prior exposure to docetaxel were selected. The dosing schedule was 30 300 mg/m 2 IV QW in combination with docetaxel administered at 75 mg/m 2 IV Q3W (ASCO meeting 2011, entitled "Safety and Activity of IPI-504 (retaspimycin hydrochloride) and docetaxel in Pretreated Patients with Metastatic Non-Small Cell - 121 - 12041-7037WO / 1014 WO Lung Cancer (NSCLC))." All patients had measurable NSCLC by RECIST criteria and Karnofsky performance status >70. The relationship between the level of HSP90x and responsiveness to IPI-504 as a monotherapy or as a combined treatment with docetaxel in NSCLC patients was 5 examined. Plasma levels of HSP90x in 27 patients were analyzed by ELISA prior to treatment. Bars representing patients with values of HSP90X protein of less than, e.g., 9.87 ng/mL (down to a minimum level tested of, e.g., 1.80 ng/mL) are assigned to the low-HSP90ax level group (represented by one asterisk in Figure 1), and bars 10 representing patients with values greater than, e.g., 9.87 ng/mL HSP90X (up to a maximum level tested of, e.g., 46.49 ng/mL) are assigned to the high HSP90aX level group and are shown without an asterisk (Figure 1). Bars show the best percentage post-treatment change in a patient's response from baseline; each bar represents a single patient. Figure 1 shows the best percent change of response in relation to 15 plasma levels of HSP90x in NSCLC patients treated with IPI-504 in combination with docetaxel. 9 out of 12 NSCLC patients with low levels of HSP90X showed an increase in lesion size in response to the combination therapy; whereas only 3 out of 15 NSCLC patients with low levels of HSP90x showed a decrease in lesion size in response to the combination therapy. Most of the patients (12 out of 15 patients) with 20 high levels of HSP90x showed an improved response (detected by a decreased lesion size). NSCLC patients showed a higher level of HSP90x before treatment, compared to normal healthy donors. Figure 2 is a graphic representation of the increased level of HSP90x (ng/mL) in the plasma of patients with non-small cell lung 25 cancer (filled triangles) compared to normal healthy donors (filled squares). The correlation between HSP90ax level and response to IPI-504 and docetaxel was examined in patients with the following cancers: rectal, NSCLC, testicular, prostate, salivary gland, pancreatic, and melanoma (Figure 3). Figure 3 shows the best percent change in target lesions from baseline in patients having each of these 30 cancers (as indicated in the x-axis) after treatment. The bar graphs are numbered 1-18 and correspond to the following cancers: rectal cancer (1), NSCLC (2), NSCLC (3), NSCLC (4), unknown (5), NSCLC (6), testicular cancer (7), NSCLC (8), unknown (9), NSCLC (10), prostate cancer (11), NSCLC (12), salivary gland cancer (13), - 122 - 12041-7037WO / 1014 WO NSCLC (14), NSCLC (15), pancreatic cancer (16), melanoma (17), and pancreatic cell (18). High levels of HSP90x protein (e.g., about 17 to about 47 ng/mL) are indicated by a double asterisk; mid-levels of HSP90x protein (e.g., about 5 to about 17 ng/mL) are indicated by a single asterisk; and low levels of HSP90X protein (e.g., 5 about 1.3 to about 5 ng/mL) are indicated by no asterisk. A marked decrease in lesion size from baseline was detected in cancer patients showing high or mid-levels of HSP90x protein, for example, patients with NSCLC, pancreatic cancer, melanoma and salivary gland cancer. NSCLC patients with low levels of HSP90X protein did not show a reduction in lesion size, and in several cases, an increase in lesion size was 10 detected. Consistent with the results in Figure 3, NSCLC patients with high levels of HSP90x showed more pronounced positive responses to the combination of IPI-504 and docetaxel (Figure 4). Figure 4 shows the best percent change in target lesions from baseline in patients with non-small cell lung cancer. Experimental conditions 15 were as described above. High levels of HSP90x protein (e.g., about 18 to about 49 ng/mL) are indicated by a double asterisk; mid-levels of HSP90X protein (e.g., about 4.6 to about 18 ng/mL) are indicated by a single asterisk; and low levels of HSP90X protein (e.g., about 1.8 to about 4.6 ng/mL) are indicated by no asterisk. Surprisingly, a clear correlation was detected in NSCLC patients with high levels of HSP90X 20 showing more pronounced positive responses to the combination of IPI-504 and docetaxel. Intermediate responses (i.e., slight to detectable increases in lesion size) were observed in NSCLC patients showing intermediate levels of HSP90x, whereas NSCLC patients with low levels of HSP90x showed clear increases in lesion size after treatment (shown by no asterisk in Figure 4). 25 The results are summarized in Figure 5, which shows a linear graph depicting the best percent change in target lesions from baseline in patients with non-small cell lung cancer relative to HSP90x plasma levels (ng/mL). As previously, high levels of HSP90x protein (e.g., about 18 to about 49 ng/mL) are indicated by a double asterisk; mid-levels of HSP90x protein (e.g., about 4.6 to about 18 ng/mL) are indicated by a 30 single asterisk; and low levels of HSP90x protein (e.g., about 1.8 to about 4.6 ng/mL) are indicated by no asterisk. A greater percent decrease in lesion was detected in - 123 - 12041-7037WO / 1014 WO patients with high plasma levels of HSP90x followed by patients with mid-plasma levels, then followed by minimum HSP90x plasma levels. Surprisingly, unlike the correlation of increased responsiveness to the combination of IPI-504 and docetaxel with respect to increased level of HSP90X, no 5 clear correlation was detected in patients undergoing IPI-504 monotherapy. Figures 6A-6B show comparison bar graphs of the best percent change in target lesions from baseline in NSCLC patients treated with the HSP90 inhibitor, IPI-504 alone (Figure 6A) or IPI-504 in combination with docetaxel (Figure 6B). Low levels of HSP90X protein (e.g., less than or equal to 16.1 ng/mL) are indicated by an asterisk; high 10 levels of HSP90x protein (e.g., greater than 16.1 ng/mL) are indicated by no asterisk. Control subjects treated with placebo are labeled as "empty" (o). The patients in this study have either wild type or unknown K-Ras NSCLC status. No clear distinction was observed between responses in NSCLC patients undergoing IPI-504 monotherapy and the levels of HSP90x (Figure 6A). These results are contrasted 15 with the increased responsiveness to the combination of IPI-504 and docetaxel, with increased level of HSP90x detected in Figure 6B in patients undergoing IPI-504 in combination with docetaxel. Similar results are seen in Figures 6C-6D, which show comparison linear graphs of the best percent change in target lesions from baseline with respect to 20 HSP90ax levels in patients with non-small cell lung cancer treated with the HSP90 inhibitor, IPI-504 alone (Figure 6C) or IPI-504 in combination with docetaxel (Figure 6D). Low levels of HSP90x protein (e.g., less than or equal to 16.1 ng/mL) are indicated by an asterisk; high levels of HSP90x protein (e.g., greater than 16.1 ng/mL) are indicated by no asterisk. The patients in this study have either wild type 25 or unknown K-Ras NSCLC status. The correlation detected between high HSP90ax levels and increased responsiveness to the combination of IPI-504 and docetaxel was examined in NCSLC patients divided according to K-Ras status. NSCLC patients having elevated HSP90X levels (e.g., greater than 16.1 ng/mL) and having either wild type or unknown K-ras 30 gene showed increased responsiveness to the combination of IPI-504 and docetaxel (Figure 7). NSCLC patients having lower HSP90ax levels (e.g., less than or equal to 16.1 ng/mL) and having either wild type or unknown K-ras gene showed decreased - 124 - 12041-7037WO / 1014 WO responsiveness to the combination of IPI-504 and docetaxel. Only a few mutant K Ras NSCLC patients were examined. Thus, the correlation between high levels of HSP90x expression and increased responsiveness to treatment with IPI-504 and docetaxel (shown above) indicates that 5 analysis of plasma HSP90ax levels can be used to predict the responsiveness of a patient to combined treatment with docetaxel and IPI-504. In contrast, no clear correlation was observed in NSCLC patients undergoing IPI-504 monotherapy. Example 3: Detailed Evaluation of Plasma HSP90a Levels in NSCLC Patients 10 Treated with IPI-504 in Combination or Monotherapy This example confirms the relationship between the level of circulating HSP90x and responsiveness to IPI-504 in patients with NSCLC described in Example 2, and provides a more detailed evaluation. Figure 8 provides a summary of the doses and dose scheduling for NSCLC 15 patients evaluated in this Example. The number of patients in each dose group is provided in the Figure. The two left-hand columns (labeled "IPI-504-03") show patients undergoing the indicated dose and schedule of IPI-504 monotherapy. The second left column depicts the NSCLC patients where the levels of HSP90a protein were evaluated. A total of 50 patients were evaluated in the HSP90 monotherapy 20 study. The two right-hand columns (labeled "IPI-504-05") show patients undergoing the indicated dose and schedule of IPI-504 therapy in combination with docetaxel. The second right column depicts the NSCLC patients where the levels of HSP90a protein were evaluated. A total of 28 patients were evaluated in the HSP90-docetaxel combination study. 25 Plasma levels of HSP90a in the NSCLC patients were analyzed by ELISA prior to treatment. The patients were also further classified according to the K-Ras mutation status, smokers vs. non-smokers, and cancer histology. Increased responsiveness to the IPI-504/docetaxel combination therapy in NSCLC patients carrying wild type K-Ras is depicted in Figure 9. Figure 9 is a bar 30 graph showing the best percent change in target lesions from baseline in NSCLC patients treated with IPI-504 in combination with docetaxel. Asterisk-labeled bars correspond to NSCLC patients carrying wild type K-Ras; whereas the remaining shaded bars represent patients carrying a K-Ras mutation or subjects with an unknown - 125 - 12041-7037WO / 1014 WO mutation status (labeled as "empty" (o)). A greater number of NSCLC patients carrying a wild type K-Ras gene showed a decrease in tumor growth upon combination treatment, compared to patients carrying a mutated K-Ras or having an unknown mutation status. 5 A summary of the responses of the 28 NSCLC patients treated with the IPI 504 and docetaxel combination is provided in Table 1. Table 1 A\l Patients 28 5 1. H SP90 >= 1 3.4 ng/L 3 430I H SP90 < 13.4 ng/mL5 6. 10 As shown in Table 1, a median HSP90ax level of, e.g., 13.4 ng/mL was detected among the 28 patients treated with IPI-504 in combination with docetaxel. Among the patients examined, 5 patients out of 28 patients responded to the treatment, i.e., by showing greater than 30% tumor reduction by RECIST, thus leading to an overall response rate (ORR) of 17.9%. 13 patients showed an HSP90ax 15 level higher than, or equal to, the median value; and 15 patients had an HSP90ax level lower than the median value. 4 out of 13 patients with a high HSP90ax level responded to the treatment, with an ORR of 30.1%, compared to 1 out of 15 patients having low levels of HSP90ax (i.e., an ORR of 6.7%). A similar correlation between responsiveness to IPI-504 and docetaxel 20 treatment and elevated HSP90ax levels in NSCLC patients as shown in Table 1 is depicted in Figure 10. The asterisk-labeled bar graphs correspond to NSCLC patients detected to have higher than median HSP90ax level; unlabeled bar graphs correspond to NSCLC patient having lower than median HSP90ax level. NSCLC patients with an HSP90ax level higher than the median value showed a greater reduction in tumor size 25 (decrease in percentage change from baseline) compared to NSCLC patients having a lower than median HSP90ax level. - 126 - 12041-7037WO / 1014 WO Table 2 shows a pronounced correlation between responsiveness to IPI-504 and docetaxel treatment and elevated HSP90ax levels in NSCLC patients that are K Ras wild type. 5 Table 2 aroup i tResponses 3R (% Al Patients1243. H SI'90 >= 1 3.4 ng/m L 7457 H SP90~ < 3.4 ng/mL 500. 12 patients carrying wild type K-Ras were evaluated to determine the responsiveness to the combination therapy in relation to the median HSP90ax level of, e.g., 13.4 ng/mL. The results are summarized in Table 2. Among the patients 10 examined, 4 out of 12 patients responded to the treatment, i.e., by showing greater than 30% tumor reduction by RECIST, thus leading to an ORR of 33.3 % (4 out of 12 ORR in all NSCLC patients). 7 patients showed an HSP90ax level higher than, or equal to, the median value; and 5 patients had an HSP90ax level lower than the median value. 4 out of 7 patients with a high HSP90ax level responded to the treatment, with 15 an ORR of 57.1 %, compared to 0 out of 5 patients having low levels of HSP90ax (i.e., an ORR ofO0 %). A similar correlation between responsiveness to IPI-504 and docetaxel treatment and elevated HSP90ax levels in NSCLC patients as shown in Table 2 is depicted in Figure 11. The asterisk-labeled bar graphs correspond to NSCLC patients 20 detected to have higher than median HSP90ax level; unlabeled bar graphs correspond to NSCLC patient having lower than median HSP90ax level. NSCLC patients with an HSP90ax level higher than the median value showed a greater reduction in tumor size (decrease in percentage change from baseline) compared to NSCLC patients having a lower than median HSP90ax level. 25 Table 3 shows a correlation between responsiveness to IPI-504 and docetaxel treatment and elevated HSP90ax levels in NSCLC patients that are smokers. - 127 - 12041-7037WO / 1014 WO Table 3 All Patients2153. H SP90 >= 13.4 ng/mL 1243. HSP90 < 13.4 ng/m L 9 11. 21 patients that are smokers were evaluated to determine the responsiveness to the combination therapy in relation to the median HSP90ax level of, e.g., 13.4 ng/mL. 5 The results are summarized in Table 3. Among the patients examined, 5 out of 21 patients responded to the treatment, i.e., by showing greater than 30 % tumor reduction by RECIST, thus leading to an ORR of 23.9 % (6 out of 25 ORR in all NSCLC patients). 12 patients showed an HSP90ax level higher than, or equal to, the median value; and 9 patients had an HSP90ax level lower than the median value. 4 out 10 of 12 patients with a high HSP90ax level responded to the treatment, with an ORR of 33.3 %, compared to 1 out of 9 patients having low levels of HSP90ax (i.e., an ORR of 11.1 %). A correlation between responsiveness to IPI-504 and docetaxel treatment and elevated HSP90ax levels in NSCLC patients (smokers vs. non-smokers) is depicted in 15 Figure 12. The asterisk-labeled bar graphs correspond to NSCLC patients that are smokers; unlabeled bar graphs correspond to NSCLC patient that are non-smokers. NSCLC patients were either K-Ras wild-type or have an unknown K-Ras status. In general, NSCLC patients that are smokers (particularly those having an HSP90ax level higher than the median value) showed a greater reduction in tumor size (decrease in 20 percentage change from baseline) compared to NSCLC, non-smoker patients having a lower than median HSP90ax level. With respect to tumor histology, lung cancer patients having a squamous cell histology showed a better response to combination treatment. Figure 13 is a bar graph depicting a comparison of responsiveness to the combined IPI-504 and docetaxel 25 treatment in lung cancer patients showing different lung cancer histologies. The following histologies were compared: 1) adenocarcinoma, 2) bronchoalveolar, 3) large cell carcinoma, 4) squamous cell carcinoma, and 5) unspecified NSCLC. Patients were either K-Ras wild-type or have an unknown K-Ras status. As shown in - 128 - 12041-7037WO / 1014 WO Figure 14, NSCLC patients having a squamous cell histology showed a greater decrease in tumor size compared to other tumor histologies. Table 4 shows a correlation between responsiveness to IPI-504 and docetaxel treatment and elevated HSP90x levels in NSCLC patients with squamous cell 5 carcinoma. Table 4 All Patients73429 H SP90 >= 13.4 ng/mL 6 350.0 HSP90 < 13.4 ng/m L I . 7 patients with a squamous cell carcimomahistology were evaluated to 10 determine the responsiveness to the combination therapy in relation to the median HSP9O0a level of, e.g., 13.4 ng/mL. The results are summarized in Table 4. Among the patients examined, 3 out of 7 patients responded to the treatment, i.e., by showing greater than 30 % tumor reduction by RECIST, thus leading to an ORR of 42.9 % (3 out of 8 ORR in all NSCLC patients). 6 patients showed an HSP90ax level higher 15 than, or equal to, the median value; and 1 patient had an HSP90ax level lower than the median value. 3 out of 6 patients with a high HSP90ax level responded to the treatment, with an ORR of 50 %, compared to 0 out of 1 patients having low levels of HSP90ax (i.e., an ORR of 0 %). A similar correlation between responsiveness to JPJ-504 and docetaxel 20 treatment and elevated HSP90ax levels in NSCLC patients as shown in Table 4 is depicted in Figure 14. The unlabeled bar graphs correspond to NSCLC patients with a squamous cell carcinoma histology detected to have higher than median HSP90ax level; the asterisk-labeled bar graph corresponds to NSCLC patient having lower than median HSP90ax level. NSCLC patients with a squamous cell carcinoma histology 25 and an HSP90ax level higher than the median value showed a greater reduction in tumor size (decrease in percentage change from baseline) compared to NSCLC patients having a lower than median HSP9O0a level. - 129 - 12041-7037WO / 1014 WO Figures 15 and 16 are linear graphs depicting the percentage change from baseline as a function of the mean HSP90x concentration (ng/mL) in NSCLC patients treated with IPI-504 in combination with docetaxel. Figure 15 includes data from all NSCLC patients (including patients carrying a K-Ras mutation); whereas Figure 16 5 includes NSCLC patients carrying either wild-type or unknown KRAS status (excludes patients carrying a KRAS mutation). In both graphs, the asterisk-labeled squares correspond to NSCLC patients having a higher than median HSP90aX level (indicated by the vertical line); the unlabeled squares correspond to NSCLC patient having lower than median HSP90ax level. In both instances, NSCLC patients with an 10 HSP90ax level higher than the median value showed a statistically significant increased reduction in tumor size (decrease in percentage change from baseline) compared to NSCLC patients having a lower than median HSP90aX level. The r2 value of the correlation was 0.164 and 0.324 of Figures 15 and 16, respectively. Figures 17 and 18 provide linear graphs depicting the percentage change from 15 baseline as a function of the mean HSP90x concentration (ng/mL) in NSCLC patients treated with IPI-504 in combination with docetaxel. The values depicted in Figures 17-18 are normalized with plasma protein values and lab albumin values, respectively. In both graphs, a single asterisk-labeled square represents an HSP90X level lower than the median value; the unlabeled square represents an HSP90aX level 20 higher than the median value. Thus, a clear correlation was detected between higher HSP90aX levels in NSCLC patients, (including all NSCLC patients, NSCLC patients with wild type K Ras, and NSCLC patients with an SCC histology) and increased responsiveness to IPI-504 in combination with docetaxel. 25 Unlike the predictive value of HSP90ax levels and therapeutic response to the combination of IPI-504 and docetaxel, no clear correlation was detected in NSCLC patients receiving IPI-504 as a monotherapy. Figure 19 is a linear graph depicting the percentage change from baseline as a function of the mean HSP90X concentration (ng/mL) in NSCLC patients treated with IPI-504 only. No clear correlation between 30 HSP90ax levels and therapeutic response to IPI-504 was detected. Figure 20 provides another visual representation of the lack of correlation between HSP90x levels and therapeutic response to IPI-504 monotherapy. It is a bar graph showing the best percent change in target lesions from baseline in NSCLC - 130- 12041-7037WO / 1014 WO patients treated with IPI-504 with high or low levels of HSP90X. Asterisk-labeled bars correspond to NSCLC patients having higher than median levels of HSP90X, whereas unlabeled bars show lower than median levels of HSP90X. The correlation between high levels of HSP90x and increased responsiveness 5 to the combination of IPI-504 and a taxane suggests that HSP90aX levels can be predictive of a patient's increased response to IPI-504 treatment in combination with a taxane, such as docetaxel. It is surprising how elevated levels of HSP90X is indicative of increased responsiveness in NSCLC patients undergoing treatment with IPI-504 in combination with a taxane; whereas no clear trend is detected in NSCLC 10 patients undergoing IPI-504 monotherapy. Example 4: Levels of HSP90aare predictive of survival in response to treatment with IPI-504 in combination with docetaxel The relationship between HSP90a level and survival of NSCLC patients 15 treated with IPI-504 was analyzed. Plasma levels of HSP90a in NSCLC patients undergoing combination therapy of IPI-504 and docetaxel, or IP-504 monotherapy, were analyzed by ELISA prior to treatment. Patient groupings were similar to those described in Examples 2 and 3. NSCLC patients with high levels of HSP90a had increased survival when 20 treated with IPI-504 in combination with docetaxel, compared to NSCLC patient with lower levels of the biomarker. A Kaplan-Meier survival estimate is depicted in Figure 21, where NSCLC patients with elevated levels of HSP90a that were greater than the median value (e.g., greater than 14.5 ng/mL) treated with IPI-504 combination therapy showed increased Overall Survival (OS) of 7.5 months compared to 4.6 25 months in those patients having plasma levels of HSP90a of less than or equal to the median (e.g., 14.5 ng/mL). A similar correlation of increased survival and high levels of HSP90a in 29 NSCLC patients receiving the combination therapy is depicted in Figure 22. In Figure 22, the distinction between high and low levels was based on a threshold of, e.g., 13.4 ng/mL. 30 Unlike the correlation between high levels of HSP90a and increased survival when treated with IPI-504 in combination with docetaxel, no clear increased survival is detected in NSCLC patient receiving IPI-504 as a monotherapy. A Kaplan-Meier survival estimate of 57 NSCLC patients receiving IPI-504 alone showed no - 131 - 12041-7037WO / 1014 WO significant difference between the patients having high and low levels of HSP90X (Figure 23). The overall survival data from the 57 NSCLC patients receiving IPI-504 alone were analyzed at various different cut offs between high and low levels of HSP90x (e.g., 5.4 ng/mL, 13.4 ng/mL, 14.5 ng/mL). 5 The correlation between levels of HSP90x and survival suggests that HSP90x levels can be used to prognosticate patient outcomes in response to IPI-504 treatment in combination with docetaxel. It is surprising how elevated levels of HSP90X is indicative of longer survival of NSCLC patients undergoing treatment with IPI-504 in combination with a taxane; whereas no clear trend is detected in NSCLC patients 10 undergoing IPI-504 monotherapy. Example 5: Levels of HSP90aas a Predictor of Tumor Responsiveness and Survival in Patients Treated with IPI-504 in Combination with Docetaxel Samples from clinical trial IPI-504-05, in which patients received IPI-504 in 15 combination with docetaxel, were analyzed using a quantitative ELISA for detection of human HSP90a in human plasma. The samples were diluted using a dilution factor of 1:25. The results obtained using the assay with diluted samples were similar to and consistent with results obtained using undiluted samples (e.g., absolute values were shifted but the rank order was similar). Furthermore, the results of both assays 20 indicated that levels of HSP90a can predict tumor responsiveness and survival in patients treated with a combination of IPI-504 and docetaxel. Absolute levels of HSP90a reported below are exemplary values calculated based on particular subject samples. It shall be understood that these values are 25 presented as examples and are not limiting. Absolute levels can vary depending on, e.g., the sample of patients, assay conditions, sample conditions (e.g., extent of hemolysis), and/or individual characteristics of the patients studied (e.g., tumor histology (e.g., squamous cell carcinoma versus adenocarcinoma), KRAS mutant status, and/or history of smoking). 30 Prediction of Tumor Responsiveness Using Median Cutoff Figures 24-25 show that levels of HSP90x predict tumor responsiveness. In Figure 24, the division between HSP90a high and HSP90a low groups was made - 132 - 12041-7037WO / 1014 WO based on a median cutoff. The median was calculated based on n=26 subjects. The median value in this particular sample was, e.g., about 70.92 ng/mL. Prediction of Tumor Responsiveness Using Optimized Cutoff 5 In Figure 25, the division between HSP90x high and HSP90x low groups was made based on an optimized cutoff. The optimized cutoff was calculated based on the same group of n=26 subjects. The optimized cutoff was calculated using the method described in Contal, C. et al.Computational Statistics & Data Analysis, 30: 253-270 (1999). In short, the data were rank ordered from lowest to highest plasma HSP90x 10 concentration. The data were split into two groups (low: those smaller than a distinct cutoff value; and high: those larger than a distinct cutoff value) based on each possible cutoff value. The optimized cutoff value was determined as the value that provided the smallest p-value (e.g., the greatest difference in survival) using a log rank test. The optimized cutoff value in this particular sample was, e.g., about 59 15 ng/mL. In one embodiment, the optimized cutoff based on survival was applied to tumor response data. Prediction of Tumor Responsiveness Considering KRAS Mutant Status In Figures 24 and 25, data from patients who were found to be carriers of 20 KRAS mutations are marked with an asterisk. The association between HSP90x levels and tumor responsiveness to treatment with the combination of IPI-504 and docetaxel was even stronger in patients who did not have known KRAS mutations. Prediction of Survival 25 Figure 26 shows the relationship between HSP90x levels and survival in patients treated with the combination of IPI-504 and docetaxel. As shown in Figure 26, the high HSP90x group had a higher probability of survival than the low HSP90x group. The division between "HSP90a high" and "HSP90a low" groups was made based on an optimized cutoff. The optimized cutoff was calculated using the method 30 described in Contal, C. et al.Computational Statistics & Data Analysis, 30: 253-270 (1999). The data were rank ordered from lowest to highest plasma HSP90x concentration. Based on each possible cutoff value, the data were split into two groups (low: those data points with values lower than a distinct cutoff value; and high: - 133 - 12041-7037WO / 1014 WO those data points with values larger than or equal to a distinct cutoff value). The optimized cutoff value was determined as the value that provided the smallest p-value (i.e., the best prediction of survival) using a log rank test. The optimized cutoff value in this particular sample was, e.g., about 59 ng/mL. 5 Example 6: Inverse Correlation Between HSP90a Serum Levels and HSP90a Tissue Levels in NSCLC Patients HSP90ax levels in tissue and in serum were assayed in a sample (n=12) of NSCLC patients that received concurrent treatment with IPI-504 and docetaxel. The 10 tissue and serum levels were found to be inversely correlated, particularly in patients who did not have (known) KRAS mutations (Figure 27). In this figure, the arrow indicates a data point from a subject with a KRAS mutation. The inverse correlation between tissue and serum HSP90ax levels suggests that if HSP90x is coming from the tumor, patients with high plasma HSP90ax levels have low tissue levels due to active 15 secretion of the protein. Example 7: Contribution of Hemolysis to HSP90a Plasma Levels and Correction of HSP90a Plasma Levels for Hemolysis HSP90x is expressed at high levels in red blood cells (RBCs). Thus, 20 experiments were conducted to investigate whether lysed RBCs contribute to HSP90x plasma levels. Influence of Hemolysis on HSP90a Plasma Levels in a Normal Donor For example, blood was collected from a normal donor using sodium heparin 25 collection tubes. Immediately after collection, the vacutainers were frozen in dry ice for 1 hour to hemolyze the sample. The sample was then thawed at room temperature and centrifuged to collect the hemolyzed plasma. A second group of vacutainers were collected at the same time from the same normal donor and centrifuged within 30 minutes to collect the non-hemolyzed plasma. The hemolyzed plasma was then 30 mixed with the non-hemolyzed plasma to obtain the % hemolysis concentrations. Each sample was prepared at a 1:50 dilution and analyzed in duplicate. Additionally, a spectrophotometric assessment of hemolysis was performed by reading the absorbance of each sample (undiluted) at 575 nm. - 134 - 12041-7037WO / 1014 WO The results indicated that hemolysis can influence the level of HSP90x detected in plasma. Correction for hemolysis can therefore improve the specificity of the assay when samples are being tested in which hemolysis is observed. 5 Influence of Hemolysis on HSP90a Plasma Levels in Patient Samples Further experiments were conducted to investigate whether lysed RBCs contribute to HSP90x plasma levels in patient samples. Whole blood samples (n=24 individual donors) from normal donors were spun down to create packed red cell pellets. These were frozen to lyse, then diluted in buffer at varying concentrations. 10 Each set of 24 normal donor dilutions was read at OD 575 nm and then these samples were run in the ELISA to determine the corresponding concentration of HSP90x. Then samples at similar dilutions for all 24 normal donors were pooled to create 8 pooled RBC lysates to cover the ELISAs linear range. These results likewise indicate that hemolysis can influence the level of HSP90x detected in plasma. 15 Correction of HSP90a Plasma Levels for Hemolysis Each patient sample is hemolyzed to a different degree. Thus, the ability of HSP90x plasma levels to predict clinical outcomes, as described herein, can be improved if a correction is carried out to account for the influence of hemolysis on 20 plasma HSP90ax level. This correction can be particularly helpful when significant levels of hemolysis and/or highly variable levels of hemolysis are observed in the samples being analyzed. It is assumed that levels of hemolysis can be extrapolated to specified levels of HSP90a across all subjects in a particular sample of subjects used to generate a 25 standard curve. Known red blood samples with hemolysis are measured using a spectrometer that measures the amount of light. The light of a wavelength passing through a solution will usually produce a relationship between the concentration and intensity of the transmitted light. This intensity of transmitted light is measured and defined as optical density (O.D.). 30 To correct for the effect of hemolysis on HSP90ax levels, in addition to the readings taken at 450 nm to determine the HSP90x concentration, optical density readings at 575 nm are taken. The value of the optical density reading at 575 nm is used to determine the RBC associated HSP90 from a standard curve (e.g., a linear - 135 - 12041-7037WO / 1014 WO curve extrapolated across all patient samples). An exemplary standard curve was generated using data from 24 normal healthy donors. The RBC-associated HSP90a level is subtracted from the overall plasma HSP90ax value as measured from the sample at O.D. 450 nm. The resulting difference 5 can be considered to provide a plasma level of HSP90a that is corrected for the amount of hemolysis in the sample. Corrected and uncorrected values can be analyzed as described herein. Incorporation by Reference 10 All publications, patents, and patent applications mentioned herein are hereby incorporated by reference in their entirety as if each individual publication, patent or patent application was specifically and individually indicated to be incorporated by reference. In case of conflict, the present application, including any definitions herein, will control. 15 Also incorporated by reference in their entirety are any polynucleotide and polypeptide sequences which reference an accession number correlating to an entry in a public database, such as those maintained by The Institute for Genomic Research (TIGR) on the worldwide web at tigr.org and/or the NationalCenter for Biotechnology Information (NCBI) on the worldwide web at ncbi.nlm.nih.gov. 20 Equivalents Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments described herein. Such equivalents are intended to be encompassed. 25 - 136 -

Claims

12041-7037WO / 1014 WO What is claimed is: 1. A method for treating a subject having non-small cell lung cancer (NSCLC), comprising: administering to the subject a therapeutically effective dose of an HSP90 inhibitor and a taxane, if the subject is identified as having a circulating level of HSP90x that is greater than or equal to a predetermined value.

2. A method for treating a subject having non-small cell lung cancer (NSCLC), comprising: (i) evaluating a circulating level of HSP90x in the subject, wherein a circulating level of HSP90x that is greater than or equal to a predetermined value is indicative of an increased likelihood to respond to an HSP90 inhibitor and a taxane; and (ii) administering to the subject a therapeutically effective dose of an HSP90 inhibitor and a taxane, if the subject is determined to have a circulating level of HSP90x that is greater than or equal to the predetermined value.

3. A method of treating a subject having non-small cell lung cancer (NSCLC) comprising: (i) determining a plasma level of HSP90x in the subject, wherein a level of HSP90x in the plasma of the subject that is greater than or equal to a predetermined value chosen from a median cutoff, an optimized cutoff, or a designated quartile is indicative of an increased likelihood to respond to an HSP90 inhibitor and a taxane; and (ii) administering a therapeutically effective dose of an HSP90 inhibitor and a taxane to the subject, if the plasma level of HSP90x in the subject is greater than or equal to the predetermined value.

4. A method of, or an assay for, identifying a subject having non-small cell lung cancer (NSCLC), as having an increased or decreased likelihood to respond to a treatment that comprises an HSP90 inhibitor and a taxane, the method comprising: determining a circulating level of HSP90x in the subject, wherein a circulating level of HSP90x in the subject that is greater than or equal to a predetermined value is indicative of an increased likelihood of a response to the treatment; and - 137 - 12041-7037WO / 1014 WO wherein a circulating level of HSP90x in the subject that is less than a predetermined value is indicative of a decreased likelihood of a response to the treatment.

5. A method of, or an assay for, determining the responsiveness of a subject having non-small cell lung cancer (NSCLC) to a treatment comprising an HSP90 inhibitor and a taxane, the method comprising: determining a circulating level of HSP90x in the subject prior to the treatment; wherein a circulating level of HSP90x that is greater than or equal to a predetermined value is indicative of an increased likelihood of a response to the treatment; and wherein a circulating level of HSP90x that is less than a predetermined value is indicative of a decreased likelihood of a response to the treatment.

6. A method of, or an assay for, evaluating a time course of disease progression in a subject with non-small cell lung cancer (NSCLC), the method comprising: determining a circulating level of HSP90x in the subject; wherein an increased circulating level of HSP90x relative to a predetermined value is indicative of longer survival; and wherein a decreased circulating level of HSP90x is indicative of a decreased survival.

7. The method of any of claims 1-6, wherein an increased circulating level of HSP90x in the subject is indicative of one or more of: a decrease in tumor growth, a decrease in tumor size, increased survival, increased overall survival, or increased progression free survival.

8. The method of any of claims 1-6, wherein the predetermined value is determined based on a level of HSP90x in a reference or control sample.

9. The method of any of claims 1-6, wherein the predetermined value is a middle or median value of HSP90x in a reference group of patients or healthy controls.

10. The method of any of claims 1-6, wherein the predetermined value is a circulating level of HSP90x in a sample obtained at two different time intervals, wherein - 138 - 12041-7037WO / 1014 WO an increase in the circulating level of HSP90x is indicative of one or more of: an increased likelihood to respond to an HSP90 inhibitor and a taxane; increased survival; or that a therapy with an HSP90 inhibitor and a taxane is to be continued.

11. The method of any of claims 1-6, wherein the subject is evaluated prior to, during, or after a treatment.

12. The method of any of claims 1-6, wherein the circulating level of HSP90X is normalized relative to a control value.

13. The method of any of claims 1-6, wherein the predetermined value is an optimized cutoff, which is calculated by selecting the cutoff associated with the smallest p value for a test statistic.

14. The method of any of claims 1-6, wherein the predetermined value is a designated quartile.

15. The method of any of claims 1-6, wherein the circulating level of HSP90X is determined from a sample that is non-hemolyzed or wherein the circulating level of HSP90x in the sample is corrected for hemolysis.

16. The method of claim 15, wherein one or more spectrophotometric optical density readings are used to assess the extent of hemolysis in the sample.

17. The method of any of claims 1-6, further comprising one, two, three, four, five, six, seven, or eight of the following: (i) detecting the presence of squamous cell carcinoma cells or tissues in a sample from the subject; (ii) determining whether the subject has a smoking history of at least 5, 10, 15, or more pack years; (iii) determining the K-Ras status in the subject; (iv) determining the LKB 1 mutation status in the subject; (v) determining the ALK mutation status in the subject; - 139 - 12041-7037WO / 1014 WO (vi) determining the B-Raf mutation status in the subject; (vii) determining mutation status at the 14q31-33 gene locus in the subject; or (viii) determining a level of tumor hypoxia or a level of a marker of tumor hypoxia in the subject.

18. The method of any of claims 1-6, further comprising one, two, or three of the following: (i) detecting the presence of adenocarcinoma or squamous cell carcinoma cells or tissues in a sample from the subject; (ii) determining whether the subject has a smoking history of at least 5, 10, 15, or more pack years; or (iii) determining a level of tumor hypoxia or a level of a marker of tumor hypoxia in the subject.

19. The method of any of claims 1-6, wherein a circulating level of HSP90X in the subject that is greater than or equal to a predetermined value, and one, two, three, four, five, six, seven, or eight of the following is indicative of an increased likelihood of a response to a treatment comprising an HSP90 inhibitor and a taxane: (i) detecting the presence of squamous cell carcinoma cells or tissues in the subject; (ii) identifying the subject as a smoker; (iii) detecting the presence of wild type K-Ras; (iv) detecting the presence of mutant type LKB 1; (v) detecting the presence of mutant type ALK; (vi) detecting the presence of mutant type B-Raf; (vii) detecting an alteration in copy number at the 14q31-33 gene locus; or (viii) detecting tumor hypoxia in the subject.

20. The method of any of claims 1-6, wherein a circulating level of HSP90X in the subject that is greater than or equal to a predetermined value, and one, two, or three of the following is indicative of an increased likelihood of a response to a treatment comprising the HSP90 inhibitor and the taxane: - 140 - 12041-7037WO / 1014 WO (i) detecting the presence of squamous cell carcinoma cells or tissues in the subject; (ii) identifying the subject as a smoker; or (iii) detecting tumor hypoxia in the subject.

21. The method of any of claims 1-6, wherein a circulating level of HSP90x in the subject that is greater than or equal to a predetermined value is indicative of an increased likelihood of a response, and the response is selected from one or more of tumor responsiveness or survival.

22. The method of claim 21, wherein said survival is overall survival or progression free survival.

23. The method of claim 21, wherein said tumor responsiveness is shrinkage of a tumor or decreased growth of a tumor.

24. The method of any of claims 1-6, wherein the circulating level of HSP90x is determined prior to treating the subject with the HSP90 inhibitor and the taxane.

25. The method of any of claims 1-4 and 6, wherein the circulating level of HSP90x is determined during treatment with an HSP90 inhibitor and a taxane.

26. The method of any of claims 1-4 and 6, wherein the circulating level of HSP90x is determined after treatment with an HSP90 inhibitor and a taxane.

27. The method of any of claims 1-6, wherein the circulating level of HSP90x is determined using a reagent which specifically binds with an HSP90x polypeptide.

28. The method of claim 27, wherein the reagent is selected from the group consisting of an antibody, an antibody derivative, and an antibody fragment.

29. The method of claim 28, wherein the circulating level of HSP90x in the sample is determined using an antibody-based detection technique selected from the - 141 - 12041-7037WO / 1014 WO group consisting of enzyme-based immunoabsorbent assay, ELISA, immunofluorescence cell sorting (FACS), immunohistochemistry, immunofluorescence (IF), western blot, affinity purification, fluorescence resonance energy transfer (FRET) imaging, antigen retrieval and microarray detection methods.

30. The method of any of claims 1-6, further comprising obtaining a sample from the subject.

31. The method of claim 30, wherein the sample is a biological sample.

32. The method of claim 30, wherein the sample is a body fluid.

33. The method of claim 30, wherein the sample is a whole blood, a plasma, or a serum sample.

34. The method of claim 33, wherein the sample is a plasma or a serum sample.

35. A method for treating a subject having non-small cell lung cancer (NSCLC), comprising: administering to the subject a therapeutically effective dose of an HSP90 inhibitor and a taxane, if the subject is identified as having a level of HSP90x that is less than or equal to a predetermined value in a tissue sample from the subject.

36. The method of any of claims 1-6, wherein the NSCLC is a relapsed or refractory NSCLC.

37. The method of claim 36, wherein the NSCLC harbors a wild type K-Ras gene or gene product.

38. The method of claim 36, wherein the NSCLC harbors one or more of: a mutation in an ALK gene or gene product chosen from an ALK rearrangement, an EML4-ALK fusion, or a p53 mutation; or has an alteration in copy number at the 14q3 1 33 gene locus. - 142 - 12041-7037WO / 1014 WO

39. The method of any of claims 1-5 and 7-38, wherein the HSP90 inhibitor is a benzoquinone or a hydroquinone ansamycin HSP90 inhibitor.

40. The method of claim 39, wherein the HSP90 inhibitor is a compound of formula 3: H, ,H OH NO N Me N Me OH H tOMe MeO Me HO M, O NH 2 3 wherein X- is chloride.

41. The method of claim 39, wherein the HSP90 inhibitor is: HO 0 H H 2 N N Me N N N H H Me"H a I'OmeMeO "0 H Me O HO "N M O O40 NH 2 or NH , , or a pharmaceutically acceptable salt thereof.

42. The method of claim 39, wherein the taxane is docetaxel or paclitaxel.

43. The method of claim 40, wherein the taxane is docetaxel or paclitaxel.

44. The method of claim 41, wherein the taxane is docetaxel or paclitaxel.

45. The method of claim 42, wherein the taxane is docetaxel. - 143 - 12041-7037WO / 1014 WO

46. The method of claim 43, wherein the taxane is docetaxel.

47. The method of claim 44, wherein the taxane is docetaxel.

48. A method for treating a subject having non-small cell lung cancer (NSCLC), comprising: administering to the subject a therapeutically effective dose of an HSP90 inhibitor and a taxane, if the subject is identified as having a circulating level of HSP90x that is greater than or equal to a predetermined value, wherein the HSP90 inhibitor is a benzoquinone or a hydroquinone ansamycin HSP90 inhibitor.

49. A kit for evaluating a sample from a lung cancer patient to detect or determine the level of HSP90x, said kit comprising: a reagent that specifically detects HSP90x in the sample; and instructions for use, wherein said instructions for use provide one or more of the following: if the level of HSP90x in the sample of the subject prior to, during, or after, treatment is greater than a predetermined value, the subject is more likely to respond to a treatment with an HSP90 inhibitor in combination with a taxane; and/or if the level of HSP90x in the sample of the subject prior to, during, or after, a treatment therapy comprising an HSP90 inhibitor and a taxane is greater than a predetermined value, the subject has an increased probability of survival. - 144 -