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WO 2016/004387 Al 7 January 2016 (07.01.2016) P O P C T

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WO 2016/004387 Al 7 January 2016 (07.01.2016) P O P C T (12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (10) International Publication Number (43) International Publication Date WO 2016/004387 Al 7 January 2016 (07.01.2016) P O P C T (51) International Patent Classification: (81) Designated States (unless otherwise indicated, for every A61P 35/00 (2006.01) kind of national protection available): AE, AG, AL, AM, AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, (21) International Application Number: BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, PCT/US20 15/039 108 DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, (22) International Filing Date: HN, HR, HU, ID, IL, IN, IR, IS, JP, KE, KG, KN, KP, KR, 2 July 2015 (02.07.2015) KZ, LA, LC, LK, LR, LS, LU, LY, MA, MD, ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, OM, (25) Filing Language: English PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SA, SC, (26) Publication Language: English SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. (30) Priority Data: 62/020,3 10 2 July 2014 (02.07.2014) US (84) Designated States (unless otherwise indicated, for every kind of regional protection available): ARIPO (BW, GH, (71) Applicant: H. LEE MOFFITT CANCER CENTER GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, ST, SZ, AND RESEARCH INSTITUTE, INC. [US/US]; 12902 TZ, UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, Magnolia Dr., Tampa, FL 336 12-9497 (US). TJ, TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, DK, EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, (72) Inventors: BOSQUET, Jesus, Gonzalez; 851 Oxen Ln, LV, MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, Iowa City, IA 52240 (US). LANCASTER, Johnathan, SM, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, Mark; - (US). GW, KM, ML, MR, NE, SN, TD, TG). (74) Agents: LADWIG, Glenn, P. et al; Saliwanchik, Lloyd & Published: Eisenschenk, P.O. Box 142950, Gainesville, FL 32614- 2950 (US). — with international search report (Art. 21(3)) 00 (54) Title: GENE EXPRESSION SIGNATURE FOR CANCER PROGNOSIS o (57) Abstract: The current invention pertains to a method for determining whether a subject suffering from a cancer is a good can o didate for a chemotherapy for the cancer, and a method of treating a subject suffering from a cancer based on the identification of the subject as a good candidate or a bad candidate for the chemotherapy. The methods comprise the steps of identifying the subject as a good candidate for a chemotherapy or a bad candidate for the chemotherapy. The methods may further include administering the chemotherapy to the subject if the subject is identified as a good candidate for the chemotherapy, or withholding the administration of the chemotherapy to the subject identified as the bad candidate for the chemotherapy. In addition to withholding the chemother - apy from the bad candidate, an alternative treatment may be administered. The current invention also provides microarray chips use - ful in practicing the claimed invention of identifying a subject suffering from a cancer as a good candidate for a chemotherapy. GENE EXPRESSION SIGNATURE FOR CANCER PROGNOSIS DESCRIPTION CROSS-REFERENCE TO RELATED APPLICATION The present application claims the benefit of U.S. Provisional Application Serial No. 62/020,310, filed July 2, 2014, which is hereby incorporated by reference herein in its entirety, including any figures, tables, nucleic acid sequences, amino acid sequences, or drawings. GOVERNMENT SUPPORT This invention was made with government support under grant number W81XWH- 08-2-0101 awarded by the US Army Medical Research and Materiel Command. The government has certain rights in the invention. BACKGROUND OF THE INVENTION Epithelial ovarian cancer (OVCA) has the highest mortality rate of all gynecologic cancers1, mainly because more than 70% of patients present with advanced stage and will have disseminated intra-peritoneal disease at diagnosis2. But also because between 20-30% will not respond to the initial treatment consisting of a combination of cytoreductive surgery and a platinum-based chemotherapy3. Even in some patients with a complete initial response to chemotherapy, the disease will recur and eventually develop resistance to multiple drugs4. Several mechanisms have been described to contribute to chemo-response including drug efflux, increased cellular glutathione levels, increased DNA repair, and drug tolerance, but the exact mechanisms are not fully defined5 7 , and there are no valid clinical biomarkers or molecular signatures that effectively predict response to chemotherapy8'9. Understanding the underlying processes could lead to the identification of prognostic signatures, which in turn, could be used to stratify patients who are likely to develop resistance to standard chemotherapy and thus could benefit from alternative strategies9. BRIEF SUMMARY OF THE INVENTION The current invention provides a method of treating a subject suffering from a cancer, the method comprising the steps of: a) comparing the expression of mRNAs corresponding to the proteins identified in Table 9 or Table 12 in a sample obtained from the subject to reference values corresponding to the mRNAs expression in a good responder to the chemotherapy and/or to reference values corresponding to the mRNAs expression in a bad responder to the chemotherapy, b) identifying the subject as a good candidate for a chemotherapy or a bad candidate for the chemotherapy, and i) administering the chemotherapy to the subject if the subject is identified as the good candidate for the chemotherapy, or ii) withholding the administration of the chemotherapy to the subject identified as the bad candidate for the chemotherapy, and optionally, administering a cancer treatment other than the chemotherapy to the subject identified as the bad candidate for the chemotherapy, wherein, the subject is the good candidate for the chemotherapy if the expression in the sample of the subject of at least 75% of the mRNAs corresponding to the proteins identified in Table 9 or Table 12 are not significantly different than the corresponding reference values for the good responder, and/or the subject is the bad candidate for the chemotherapy if the expression in the subject of more than 25% of the mRNAs corresponding to the proteins identified in Table 9 or Table 12 are significantly different than the corresponding reference value for a bad responder. Prior to the comparison step, the method may further comprise the step of obtaining the sample from the subject. Prior to the comparison step, and after a sample is obtained from the subject, the method may further comprise measuring (quantifying) the expression of mRNAs corresponding to the proteins identified in Table 9 or Table 12 in the sample obtained from the subject. The current invention also provides microarray chip comprising mRNAs corresponding to proteins involved in cellular signaling pathways directly associated with responsiveness to chemotherapy for treatment of a cancer, the microarray chip consisting essentially of oligonucleotides corresponding to the mRNAs corresponding to the proteins identified in Table 9 or Table 12. The microarray chips of the current invention are useful in practicing the claimed invention of identifying a subject suffering from a cancer as a good candidate for chemotherapy. BRIEF DESCRIPTION OF THE DRAWINGS The patent or application file contains at least one drawing executed in color. Copies of this patent or patent application publication with color drawing(s) will be provided by the Patent and Trademark Office upon request and payment of the necessary fee. Figures 1A-1C show consensus matrices of the final signature model. Figure 1A: Consensus matrix of the final model including 422 genes, suggesting and optimal and more robust result, with limited overlap between clusters, for clustering with k-factor = 2. Figure IB: Cophenetic correlation coefficients representation, with an optimal result for k=2. Figure 1C: Other consensus matrices for k=3 to k=6 showing less harmonious models. Figures 2A-2E show validation of the NMF consensus clustering in independent publicly available databases. In all of them we used 422 genes included the final model. All of them also showed robust clustering with k = 2, and very limited overlap between clusters. Other consensus matrices for k=3 to k=6 were less harmonious (not shown). All cophenetic correlation coefficients had optimal results for k=2 (not shown). The level of agreement (kappa coefficient) for placement of an individual gene in the same cluster than in TCGA analysis are also shown for each dataset. Figure 2A: GSE9891 database 15 . Figure 2B: GSE3149 database 14 . Figure 2C: GSE26712 database 18. Figure 2D: GSE23554 database 12 . Figure 2E: GSE17260 database 17 . Figure 3 shows gene expression correlation matrix of the 422 and association with pathway analysis. Pathway analysis of both clusters showed an overrepresentation of cellular signaling and immune response pathways in cluster # 1 (blue), and DNA repair/replication within the context of cell cycle pathways in cluster #2 (yellow). Figure 4 shows gene expression profile of genes included in cluster # 1 and #2 and their association with significant pathways identified with enrichment pathway analyses. Cluster 1: significantly associated with cell signaling (blue), immune response (yellow) and a variety of metabolic pathways (purple). Cluster 2 : significantly associated with DNA repair/replication and cell cycle (green), pathways in cancer (red) and a cell adhesion/cytoskeleton pathways (maroon). Figure 5. Multivariate analysis of clinical factors affecting survival in TCGA database. Kaplan-Meier curve representing survival of patients with CR versus patients with IR (graph). Table with independent clinical variables for survival in TCGA: chemo-response is the most significant of all of them with a p-value <10-15 (table).
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