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WO 2016/089883 Al 9 June 2016 (09.06.2016) P O P C T

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WO 2016/089883 Al 9 June 2016 (09.06.2016) 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 2016/089883 Al 9 June 2016 (09.06.2016) P O P C T (51) International Patent Classification: (81) Designated States (unless otherwise indicated, for every C12N 15/113 (2010.01) C12Q 1/68 (2006.01) kind of national protection available): AE, AG, AL, AM, A61K 31/713 (2006.01) A61P 35/00 (2006.01) AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, (21) International Application Number: DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, PCT/US20 15/063206 HN, HR, HU, ID, IL, IN, IR, IS, JP, KE, KG, KN, KP, KR, (22) International Filing Date: KZ, LA, LC, LK, LR, LS, LU, LY, MA, MD, ME, MG, 1 December 2015 (01 .12.2015) MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, OM, PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SA, SC, (25) Filing Language: English SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, (26) Publication Language: English TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. (30) Priority Data: (84) Designated States (unless otherwise indicated, for every 62/085,937 1 December 2014 (01. 12.2014) US kind of regional protection available): ARIPO (BW, GH, GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, ST, SZ, (71) Applicant (for all designated States except US) : NO- TZ, UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, VARTIS AG [CH/CH]; 35 Lichtstrasse, 4056 Basel (CH). 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; and LV, MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, (71) Applicants (for US only): MOUNIR, Zineb [CA/US]; SM, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, Novartis Institutes for Biomedical Research Inc., 250 Mas GW, KM, ML, MR, NE, SN, TD, TG). sachusetts Avenue, Cambridge, MD 02139 (US). PAGLIARINI, Raymond [US/US]; Novartis Institutes for Published: Biomedical Research Inc., 250 Massachusetts Avenue, — with international search report (Art. 21(3)) Cambridge, MD 02139 (US). (74) Common Representative: NOVARTIS AG; 35 Licht strasse, 4056 Basel (CH). [Continued on next page] (54) Title: COMPOSITIONS AND METHODS FOR DIAGNOSIS AND TREATMENT OF PROSTATE CANCER (57) Abstract: The invention provides novel personalized therapies, kits, transmittable forms of information and meth ods for use in treating subjects having TMPRSS2:ERG posit ive prostate cancer, which we show is amenable to therapeut ic treatment with a PRMT5 inhibitor. Kits, methods of screening for candidate PRMT5 inhibitors, and associated methods of treatment are also provided. w o 2016/089883 A llll II II 11III III III 11II II III III II I II before the expiration of the time limit for amending the claims and to be republished in the event of receipt of amendments (Rule 48.2(h)) COMPOSITIONS AND METHODS FOR DIAGNOSIS AND TREATMENT OF PROSTATE CANCER TECHNICAL FIELD [00 1] The present invention provides novel diagnostic and treatment methods for the TMPRSS2:ERG positive prostate cancer. BACKGROUND [002] The ERG (ETS-related gene) proto-oncogene is overexpressed in a majority of prostate tumors as a result of a gene fusion involving TMPRSS2 and ERG. Petrovics et al. 2005 Oncogene 24: 3847-3852; Tomlins et al. 2005 Science 310 : 644-647; Kumar-Sinha et al. 2008 Nat. Rev. Cancer 8 : 497-51 1. The TMPRSS2/ERG fusion results in the overexpression of N-terminally truncated or full-length forms of ERG. Klezovitch et al. 2008 Proc. Natl. Acad. Sci. USA 105: 2105-21 10; and Sun et al. 2008 Oncogene 27: 5348-5353. Various studies have underscored the causative oncogenic function of ERG in prostate cancer. Klezovitch et al. 2008 Proc. Natl. Acad. Sci. USA 105: 2105-21 10; Tomlins et al. 2008 Neoplasia 10: 177-188; Sun et al. 2008 Oncogene 27: 5348-5353; Wang et al. 2008 Cancer Res. 68: 8516-24. [003] Poor disease outcome for subjects with tumors harboring duplications of TMPRSS2/ERG fusions or chromosomal losses (Edel) associated with the fusion event has been highlighted. Attard et al. 2008 Oncogene 27: 253-263; FitzGerald et al. 2008 BMC Cancer 8: 230; Mehra et al. 2008 Cancer Res 68: 3584-3590. [004] An unmet medical need thus exists for new treatments for TMPRSS2:ERG positive prostate cancer. SUMMARY OF THE INVENTION [005] The present invention provides methods of treating a TMPRSS2:ERG-positive prostate cancer comprising administering to a subject in need thereof a composition comprising a PRMT5 inhibitor. The present invention further provides methods of patient seclection, treatment response evaluation, and screening assays. The present invention is based, in part, on the discovery that the arginine methyltransferase PRMT5 is an ERG protein interactor necessary for TMPRSS2:ERG-positive prostate cancer cell proliferation. Functional analysis of ERG-dependent PRMT5 function in prostate cancer deomonstrates that ERG binds and recruits PRMT5 to methylate AR on arginine 761 (R761), which then blocks AR binding to its target genes and transcriptional activity. This inhibitory function of PRMT5 on AR is dependent on ERG expression and DNA binding function, and is selective to TMPRSS2:ERG-positive prostate cancer cells. These effects are mediated through PRMT5 catalytic activity. [006] Accordingly, the TMPRSS2:ERG gene fusion is a biomarker that can be used to predict a patient's sensitivity to PRMT5 inhibition treatment in prostate cancer. AR arginine methylation on 761 can be used as a diagnostic tool to differentiate among TMPRSS2:ERG-positive prostate cancers; where prostate cancers with "active" ERG would have elevated AR arginine methylation levels (e.g., methylation at R761 of AR) while those with "inactive" ERG would show lower to undetectable AR arginine methylation. Such stratification based on ERG activity can show diagnostic value in prostate cancer. [007] According to a first aspect, the invention provides a method for inhibiting the proliferation of TMPRSS2:ERG positive prostate cancer cells in a subject in need thereof is provided, the method comprising the step of administering to the subject a PRMT5 inhibitor in an amount that is effective to inhibit the proliferation of the TMPRSS2:ERG positive prostate cancer cells. Such a method can selectively inhibit the proliferation of TMPRSS2:ERG positive prostate cancer cells (e.g., the method can inhibit proliferation of TMPRSS2:ERG positive prostate cancer cells with a 5-fold, 10-fold, 20-fold, 30-fold, 40- fold, 50-fold, 100-fold or more efficacy or efficiency than it can inhibit cells which are not TMPRSS2:ERG positive prostate cancer cells). [008] Prostate cancer cells are determined to be TMPRSS2:ERG-positive by techniques described herein or known in the art, for example, detection of methylation of R761 of AR, immunohistochemistry utilizing an anti-TMPRSS2:ERG antibody or derivative thereof, and/or genomic sequencing, and/or nucleic acid hybridization or amplification utilizing at least one probe or primer comprising a sequence of at least 12 contiguous nucleotides (nt) of a sequence of a TMPRSS2:ERG fusion (as known in the art, e.g., Perner et al. 2006 Cancer Res. 66: 8337-8341; Demichelis et al. 2007 Oncogene 26: 4596-4599), wherein the primer is no longer than about 30 nt, about 50 nt, or about 100 nt in length. [009] In one embodiment, the invention provides use of a molecule that inhibits the cellular function of the PRMT5 protein for the treatment of TMPRSS2:ERG positive prostate cancer. [00 10] Also provided is a use of a molecule that inhibits the cellular function of the PRMT5 protein for the manufacture of a medicament for treating TMPRSS2:ERG positive prostate cancer. [001 1] The PRMT5 inhibitor may be selected from the group consisting of: a RNA inhibitor (e.g., a RNAi agent), a CRISPR, a TALEN, a zinc finger nuclease, an mRNA, an antibody or derivative thereof, a chimeric antigen receptor T cell (CART) or a low molecular weight (LMW) compound. [0012] The PRMT5 inhibitor may be selected from the group consisting of: an antibody or derivative thereof, or a low molecular weight compound. [0013] According to an embodiment, the method according to the first aspect comprises administering to a subject in need thereof, a PRMT5 inhibitor in combination with a second therapeutic agent. [0014] In an embodiment, the second therapeutic agent is an anti-cancer agent, anti allergic agent, anti-nausea agent (or anti-emetic), pain reliever, or cytoprotective agent. [00 15] According to one embodiment, the second therapeutic agent is an anti-cancer agent selected from the list consisting of: an Androgen Receptor antagonist, abiraterone, enzalutamide, bicalutamide, flutamide, HDAC inhibitor, fluorouracil (5-FU) and irinotecan, a HDM2 inhibitor, a purine analogue, 6-thioguanine, 6-mercaptopurine, and CDK4 inhibitors, including, but not limited to, LEE01 1, and inhibitors of HDM2i, PI3K/mTOR-I, MAPKi, RTKi, EGFRi, FGFRi, METi, IGFiRi, JAKi, and WNTi. In various embodiments, the anti cancer agent is known in the art, and/or known to be effective against prostate cancer cells. [00 16] According to a second aspect, the invention provides a method of determining if a subject afflicted with prostate cancer will respond to therapeutic treatment with a PRMT5 inhibitor is provided, the method comprising the steps: a) evaluating a test sample obtained from said subject for TMPRSS2:ERG positivity, wherein TMPRSS2:ERG positivity indicates that the subject will respond to therapeutic treatment with a PRMT5 inhibitor; wherein the method comprises any one or more of the following optional steps: b) determining the level and/or activity of PRMT5 in the subject, wherein steps a) and b) can be performed in any order; c) administering a therapeutically effective amount of a PRMT5 inhibitor to the subject; and d) determining the level and/or activity of PRMT5 in the subject following step c), wherein a decrease in the level and/or activity of PRMT5 is correlated with the inhibition of the proliferation of the cancer, and wherein steps c) and d), if performed, are performed after steps a) and b).
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