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WO 2012/135397 A2 4 October 2012 (04.10.2012) P O P C T (12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization II International Bureau (10) International Publication Number (43) International Publication Date WO 2012/135397 A2 4 October 2012 (04.10.2012) P O P C T (51) International Patent Classification: AO, AT, AU, AZ, BA, BB, BG, BH, BR, BW, BY, BZ, C12Q 1/68 (2006.01) CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, HN, (21) International Application Number: HR, HU, ID, IL, IN, IS, JP, KE, KG, KM, KN, KP, KR, PCT/US20 12/03 1047 KZ, LA, LC, LK, LR, LS, LT, LU, LY, MA, MD, ME, (22) International Filing Date: MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, 29 March 2012 (29.03.2012) OM, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SC, SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, TR, (25) Filing Language: English TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. (26) Publication Language: English (84) Designated States (unless otherwise indicated, for every (30) Priority Data: kind of regional protection available): ARIPO (BW, GH, 61/468,700 29 March 201 1 (29.03.201 1) US GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, SZ, TZ, 61/468,710 29 March 201 1 (29.03.201 1) US UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, (72) Inventors; and DK, EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, (71) Applicants : LISANTI, Michael, P. [US/US]; 1104 Rod LV, MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, man Street, Philadelphia, PA 19147 (US). SOTGIA, Fed- SM, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, erica [US/US]; 1104 Rodman Street, Philadelphia, PA GW, ML, MR, NE, SN, TD, TG). 19147 (US). Published: (74) Agents: UDAL, Robert, P. et al; Morgan, Lewis & — without international search report and to be republished Bockius LLP, 1701 Market Street, Philadelphia, PA upon receipt of that report (Rule 48.2(g)) 19103-2921 (US). (81) Designated States (unless otherwise indicated, for every kind of national protection available): AE, AG, AL, AM, < | (54) Title: LACTATE-AND KETONES-INDUCED GENE SIGNATURES AND USE THE SAME FOR DIAGNOSING DISEASE AND PREDICTING CLINICAL OUTCOME Λ (57) Abstract: The present invention, at least in part, is directed to a method for discovering a biological marker (biomarker) of any 2 cancer whose growth may be modulated by mitochondrial oxidative metabolism. In certain embodiments, the method comprises (a) —- contacting a set of at least one or more metabolites (e.g., 3-hydroxybutyrate or lactate or acetoacetate or oxaloacetate or citrate or a- ketoglutarate or glutamine or combinations thereof) to a first sample of a cancer cell line, a test cancer cell line; (b) assessing a level of gene expression pattern in the test cancer cell line; and (c) comparing the level of gene expression pattern of the test cancer cell line with a level of gene expression pattern in a second sample of the same cancer cell line not treated with the set of one or more metabolites, a control cancer cell line, whereby a difference between the level of the gene expression pattern in the test cancer cell line and the level of gene expression pattern in the control cancer cell line is a biomarker indicating mitochondrial oxidative meta - bolism in the cancer represented by the cancer cell. LACTATE- AND KETONES-INDUCED GENE SIGNATURES AND USE OF THE SAME FOR DIAGNOSING DISEASE AND PREDICTING CLINICAL OUTCOME FIELD OF THE INVENTION [0100] This invention relates to the fields of oncology and medicine. More specifically, the invention provides biomarkers and methods of use thereof which aid the clinician in identifying those patients most likely to benefit from certain treatment regimens. The markers disclosed herein are also useful in assays to identify therapeutic agents useful for the treatment of malignancy. BACKGROUND OF THE INVENTION [0101] The pharmaceutical industry spends billions worldwide on research and development of new drugs, but only a handful, 5 to 10%, of drugs entering the clinical phase of drug development get approved for marketing. Consequently, the average cost per successful drug development program remains unacceptably high. This average cost per successful drug development is high in part because most of the invested capital spent per drug is related to drug failures along the pipeline development path. [0102] An important reason for the high failure rate in clinical trials is the poor predictive value of currently used screening technologies for biological validation, pharmacological testing, and screening for success or failure of chemical entities and biologies in clinical trials involving human subjects. These screening technologies are based on in vitro cell-based screening models and in vivo animal models, which often lack or inadequately represent the clinical disease phenotype of the patients in which the tested chemical entities or biologies are intended to be used in the future. Therefore, success of these chemical entities or biologies in these models does not necessarily translate into clinical success in patients. Hence, the majority of chemical entities or biologies, while successful in these preceding screening and animal models, fail in clinical trials, particularly in late phase II and phase III trials (see, e.g., New Drug Development: A Regulatory Overview, Revised 5th edition. Ed. Mathieu M . Parexel, publishers). It has been estimated that more than 90% of new chemical entities (NCEs) fail in clinical trials, of which approximately two thirds fail for pharmacodynamic reasons (lack of efficacy and/or an unacceptable adverse event profile), the remaining third fail for pharmacokinetic reasons (see, e.g., Houlihan, Lokey, Howard& Zukin, Advanced Valuation Techniques in Life Sciences, February 2001). DB1/ 694375 16.1 [0103] Accordingly, many needs remain unmet in various aspects of drug development and disease treatment, including drug discovery, validation of candidate therapeutic targets, diagnosis and/or clinical classification of patients. BRIEF SUMMARY OF THE INVENTION [0104] The invention provides, at least in part, biomarkers and methods of use thereof which aid the clinician in identifying those patients most likely to benefit from certain treatment regimens. The markers disclosed herein are also useful in assays to identify therapeutic agents useful for the treatment of malignancy, including breast cancer and prostate cancer. [0105] In one aspect, the application discloses gene sets comprising genes which are differentially expressed in test samples derived from subjects having cancer, including subjects having different classes of cancer or subtypes of the same cancer, including subjects having different subtypes of breast cancer. In certain embodiments, the cancer subtypes are associated with different clinical outcomes or prognoses. Depending on the expression level of the genes in a test sample (derived from the cancer patients or from NCI-60 cell lines), the cancer (e.g., breast cancer) subtype is predicted to be associated with a good prognosis, a mixed prognosis or a poor prognosis. In alternative embodiments, the cancer subtypes are differentially associated with recurrence and/or metastasis and/or overall survival. [0106] Accordingly, in one aspect, the application provides a method of diagnosing a cancer, including breast cancer, and/or a cancer subtype in a cancer patient. [0107] In another embodiment the application provides a method of providing a prognosis. In one embodiment, the method comprises (a) culturing cancer cells derived from a sample obtained from a cancer patient in the presence of a set of at least one high-energy metabolite; and (b) assessing gene expression levels in the cultured cancer cells; and (c) comparing the gene expression levels of the cancer cell culture with the gene expression levels in a control sample, whereby a difference between the gene expression levels in the cancer cell culture and the gene expression levels of the control cell culture is indicative of the clinical outcome. In one embodiment, the application provides a method of predicting or diagnosing recurrence. In another embodiment the application provides a method of predicting metastasis. In yet another embodiment the application provides a method of predicting decreased overall survival. [0108] In some embodiments, the application provides genes whose expression levels correlate to benign or malignant states in various cells and/or tissues, including the epithelial cells, including mammary epithelial cells (e.g., carcinoma), the bone, the muscle and other connective D 1/ 09437516.1 tissues (e.g., sarcoma), the lymphatic system (e.g., lymphoma), the blood cells and/or blood precursor cells (e.g., leukemia) and the pigment-providing cells (e.g., melanoma). In some embodiments the tumor cell is breast cancer tumor cell. [0109] Another aspect of the present invention provides a method for selecting a therapeutic strategy for treating a cancer patient, the method comprising identifying a therapeutic agent which inhibits metabolite-induced gene expression pattern of at least a set of genes selected from those listed in at least one table from selected from Tables 1-7, wherein the set of genes are expressed cancer cells, derived from the cancer patient, cultured in the presence of at least one or more metabolites, wherein the therapeutic agent which inhibits metabolite-induced gene expression pattern is selected for treating the cancer patient. [0110] A method for evaluating gene expression, the method comprising treating an in vitro culture of cancer cells with a set of at least one high-energy metabolite (such as ketones or lactate); and assessing changes in gene expression resulting from the treatment with said set of at least one high-energy metabolite; wherein said method comprises generating labeled polynucleotide molecules corresponding to cancer genes having changes in expression resulting from the treatment with said set of at least one high-energy metabolite; and wherein said method further comprises applying said labeled molecules to a microarray having immobilized human genes to evaluate gene expression.
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