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WO 2014/135655 Al 12 September 2014 (12.09.2014) P O P C T

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WO 2014/135655 Al 12 September 2014 (12.09.2014) 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 2014/135655 Al 12 September 2014 (12.09.2014) P O P C T (51) International Patent Classification: (81) Designated States (unless otherwise indicated, for every C12Q 1/68 (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/EP2014/054384 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, 6 March 2014 (06.03.2014) KZ, LA, LC, LK, LR, LS, LT, LU, LY, MA, MD, ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, (25) Filing Language: English OM, PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SA, (26) Publication Language: English SC, SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, (30) Priority Data: ZW. 13305253.0 6 March 2013 (06.03.2013) EP (84) Designated States (unless otherwise indicated, for every (71) Applicants: INSTITUT CURIE [FR/FR]; 26 rue d'Ulm, kind of regional protection available): ARIPO (BW, GH, F-75248 Paris cedex 05 (FR). CENTRE NATIONAL DE GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, SZ, TZ, LA RECHERCHE SCIENTIFIQUE [FR/FR]; 3 rue UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, TJ, Michel Ange, F-75016 Paris (FR). TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, DK, EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, LV, (72) Inventors: RADVANYI, Francois; 36 rue des Potiers, F- MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, SM, 92260 Fontenay Aux Roses (FR). REBOUISSOU, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, GW, Sandra; 42 rue des Cordelieres, F-75013 Paris (FR). KM, ML, MR, NE, SN, TD, TG). KAMOUN, Aurelie; 4 1 avenue de Saint Mande, F-75012 Paris (FR). ALLORY, Yves; 40 rue Sedaine, F-7501 1 Par Published: is 69 (FR). DE REYNIES, Aurelien; boulevard Saint- — with international search report (Art. 21(3)) Michel, F-75005 Paris (FR). BERNARD-PIERROT, Isa- belle; 8 rue Francois Rolland, F-94130 Nogent sur Marne — before the expiration of the time limit for amending the (FR). LEBRET, Thierry; 10 chemin des Biloises, F- claims and to be republished in the event of receipt of 78300 Bougival (FR). amendments (Rule 48.2(h)) (74) Agents: PIERRU, Benedicte et al.; Becker & Associes, — with sequence listing part of description (Rule 5.2(a)) 25, rue Louis le Grand, 75002 Paris (FR). (54) Title: COMPOSITIONS AND METHODS FOR TREATING MUSCLE-INVASIVE BLADDER CANCER (57) Abstract: The present invention relates to a method to classify patients suffering from a muscle-invasive bladder cancer for therapeutic intervention, in particular for selecting a patient afflicted with a muscle-invasive bladder cancer for a treatment compris - ing an EGFR kinase inhibitor and/or capecitabine. Compositions and methods for treating muscle-invasive bladder cancer FIELD OF THE INVENTION The present invention relates to the field of medicine, in particular of oncology. It relates to a new method to classify patients suffering from a muscle-invasive bladder cancer for therapeutic intervention. BACKGROUND OF THE INVENTION Bladder carcinoma is one of the most common cancers in North America and Europe, accounting for approximately 200,000 new cases and 65,000 deaths in these regions in 2008. Bladder carcinoma may present as a non-muscle-invasive (70-80% of cases) or muscle-invasive (20-30% of cases) disease, with highly divergent outcomes. Most patients with non-muscle- invasive bladder cancers (NMIBC) suffer multiple recurrences of the disease without developing a muscle-invasive neoplasm. In contrast, muscle-invasive bladder cancer (MIBC) is a major clinical issue, with cancer-related deaths of 40-50% at five years for patients with organ-confined tumors and more than 80% for those with lymph node involvement or distant metastasis. Radical cystectomy is the standard treatment for MIBC. The addition of neoadjuvant and/or adjuvant chemotherapy has very modest benefits for overall survival (Sternberg et al, 2012). Iterative bladder resection and radiotherapy alone are generally considered as palliative treatment options for patient unfit for cystectomy or as part of a multimodal bladder-preserving approach (Bellmunt et al., 2010). Improvements in understanding the molecular mechanisms involved in bladder carcinoma have highlighted several potential molecular treatment targets, but no targeted treatment for MIBC is currently used in clinical practice (Dovedi and Davies, 2009). Clinical trials based on targeted therapies, either alone or in combination with conventional chemotherapy, have been largely unsuccessful (Bellmunt and Petrylak, 2012; Necchi et al, 2012; Pruthi et al, 2010; Wong et al, 2012). In particular, autocrine-mediated EGFR signaling has been shown to play an essential role in normal urothelium repair and its involvement in bladder carcinogenesis has been suggested, as the overexpression of EGFR and its ligands has been associated with advanced tumor grade/stage and poor clinical outcome (Chow et al, 2001; Thogersen et al, 2001). Moreover, preclinical studies in human bladder cancer cell lines have identified a spectrum of sensitivity to EGFR inhibitors (Adam et al., 2009; Black et al., 2008). However, recent phase II clinical trials in neoadjuvant or adjuvant settings have suggested that EGFR inhibitors have limited effects in patients with MIBC (Pruthi et al, 2010; Wong et al, 2012). All clinical trials using EGFR inhibitors have been performed in unselected MIBC patients since up to now, no predictive factors of response have been identified. Several gene expression profiling studies have revealed a high degree of molecular diversity in bladder carcinomas, including MIBC (Blaveri et al, 2005; Dyrskjot et al, 2003; Dyrskjot et al, 2007; Lindgren et al., 2010; Sjodahl et al., 2012), and patients with a particular tumor subtype might benefit from a targeted treatment considered ineffective in an unselected patient population (Baselga, 2008). As MIBC is a highly heterogeneous disease in both molecular and clinical terms, tumor stratification is a key issue in the identification of appropriate targeted treatments. In particular, a stratified approach to anti-EGFR therapy for MIBC may improve treatment efficacy. There is thus a strong need to provide reliable markers that could be used to stratify MIBC and to select patients for successful targeted therapies and in particular anti-EGFR therapy. SUMMARY OF THE INVENTION Towards a stratified approach to bladder cancer therapy, the inventors searched for clinically-relevant molecularly-homogeneous subgroups of MIBC. They identified a subgroup of particularly aggressive MIBC tumors wherein the EGFR pathway was deregulated and they further provided evidence of a relationship between this subgroup of MIBC and sensitivity to anti-EGFR drugs. Accordingly, in a first aspect, the present invention concerns a method for determining whether a muscle-invasive bladder cancer has a basal-like phenotype, wherein the method comprises (i) determining the expression level of KRT5, KRT6A and/or KRT6B and the expression level of nuclear FOXA1 in a cancer sample; and/or (ii) determining the expression level of at least 2 genes selected from the group consisting of PI3, KRT6B, CSTA, DSC2, MT1X, RAB38, SFN, SAMD9, EGFR, CD44, IL1RAP, DSP, PKP1, SERPINB7, CELSR2, DUSP7, TBC1D2, ARL4D, IPPK, MTSS1 and RGS20 genes, and the expression level of at least 2 genes selected from the group consisting of PHCl, THYNl, TACCl, PPAP2B, NRXN3, GNA14, ZFHX3, TLE2, MAML3, EPS8, CACNA1D, RAB15, MAN1C1, SORLl, CHN2, TGFBR3, CAB39L, LIMCH1 and BAMBI genes, in a cancer sample; and/or (iii) determining the expression level of at least one exon selected from the group consisting of the exons of SEQ ID NO: 23 to 41, in a cancer sample; and/or (iv) determining the DNA methylation status of at least 4 CpG islands selected from the group consisting of CpG islands listed in Table 7 in a cancer sample; and/or (v) determining the DNA methylation status of at least 4 GpC sites selected from the group consisting of GpC sites listed in Table 9 in a cancer sample; and/or (vi) determining the expression level of TGM1 gene in a cancer sample, thereby determining whether a muscle-invasive bladder cancer has a basal-like phenotype. Preferably, the method comprises determining the expression level of K T5, K T6A and/or K T6B and the expression level of nuclear FOXAl in a cancer sample, the expression of K T5, K T6A and/or K T6B and the absence of nuclear FOXAl being indicative that the muscle-invasive bladder cancer has a basal-like phenotype. In particular, the expression level of K T5, K T6A and/or K T6B and the expression level of nuclear FOXAl may be assessed by immunohistochemistry. In a particular embodiment, the method comprises determining the expression level of PKP1, IPPK, MAML3 and TGFBR3 genes in a cancer sample, high expression level of PKP1 and IPPK genes and low expression level of MAML3 and TGFBR3 genes, being indicative that the muscle-invasive bladder cancer has a basal-like phenotype. In another particular embodiment, the method comprises determining the expression level of the exon of SEQ ID NO: 24 in a cancer sample, low expression level of said exon being indicative that the muscle-invasive bladder cancer has a basal-like phenotype. In another particular embodiment, the method comprises determining the expression level of the exon of SEQ ID NO: 37 in a cancer sample, high expression level of said exon is indicative that the muscle-invasive bladder cancer has a basal-like phenotype.
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