WO 2016/038550 Al 17 March 2016 (17.03.2016) P O P C T
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(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 2016/038550 Al 17 March 2016 (17.03.2016) P O P C T (51) International Patent Classification: (81) Designated States (unless otherwise indicated, for every C12N 15/113 (2010.01) A61K 31/713 (2006.01) kind of national protection available): AE, AG, AL, AM, G01N 33/574 (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) Number: International Application DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, PCT/IB2015/056902 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, >September 2015 (09.09.2015) 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 62/049,004 11 September 2014 ( 11.09.2014) US kind of regional protection available): ARIPO (BW, GH, 62/13 1,437 11 March 2015 ( 11.03.2015) US GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, ST, SZ, TZ, UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, (71) Applicant (for all designated States except US) : NO- TJ, TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, VARTIS AG [—/CH]; Lichtstrasse 35, CH-4056 Basel DK, EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, (CH). LV, MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, SM, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, (72) Inventors; and GW, KM, ML, MR, NE, SN, TD, TG). (71) Applicants (for US only): MAVRAKIS, Konstantinos John [US/US]; Novartis Institutes for BioMedical Re Declarations under Rule 4.17: search, Inc., 250 Massachusetts Avenue, Cambridge, MA — as to applicant's entitlement to apply for and be granted a 02139 (US). MCDONALD, Earl, III [US/US]; Novartis patent (Rule 4.1 7(H)) Institutes for BioMedical Research, Inc., 250 Massachu setts Avenue, Cambridge, MA 02139 (US). STEGMEI- Published: ER, Frank Peter [US/US]; Novartis Institutes for Bio — with international search report (Art. 21(3)) Medical Research, Inc., 250 Massachusetts Avenue, Cam bridge, MA 02139 (US). — before the expiration of the time limit for amending the claims and to be republished in the event of receipt of (74) Agent: NOVARTIS AG; Lichtstrasse 35, CH-4056 Basel amendments (Rule 48.2(h)) (CH). © © v o (54) Title: INHIBITION OF PRMT5 TO TREAT MTAP -DEFICIENCY-RELATED DISEASES (57) Abstract: The invention provides novel personalized therapies, kits, transmittable forms of information and methods for use in treating patients having cancer, wherein the cancer is MTAP -deficient and/or MTA-accumulating and thus amenable to therapeutic o treatment with a PRMT5 inhibitor. Kits, methods of screening for candidate PRMT5 inhibitors, and associated methods of treatment are also provided. INHIBITION OF PRMT5 TO TREAT MTAP-DEFICIENCY-RELATED DISEASES TECHNICAL FIELD [001] The present invention provides novel compositions, as well as diagnostic and treatment methods for diseases related to MTAP deficiency and/or MTA accumulation, including, but not limited to, types of cancer. BACKGROUND [002] Many types of cancer are associated with a poor prognosis. [003] Pancreatic cancer is associated with a poor long-term survival rate of only 10% to 15% after resection. Patients with positive microscopic resection margins have a worse survival. The median survival was 19.7 months with chemotherapy versus 14.0 months without. See, e.g., Neoptolemos et al. 2001 Ann. Surg. 234: 758-768. [004] Mesothelioma is a rare form of cancer that develops from cells of the mesothelium, the protective lining that covers many of the internal organs of the body. Mesothelioma is most commonly caused by exposure to asbestos. While mesothelioma is still relatively rare, rates have increased in the last twenty years. One study showed a survival rate of only 38% at 2 years and 15% at 5 years (median 19 months). See, e.g., Sugarbaker et al. 1999 J. Thorac. Card. Surg. 117: 54-65. [005] Glioblastoma is the most common and most aggressive malignant primary brain tumor in humans. It involves glial cells and accounts for half of all brain tumor cases and a fifth of all intracranial tumors. Treatment can involve surgery, radiation and chemotherapy. However, median survival with treatment is only 15 months. [006] An unmet medical need exists for new treatments for these and other types of cancer. [007] There is an increasing body of evidence that suggests a patient’s genetic profile can be determinative to a patient’s responsiveness to a therapeutic treatment. Given the numerous therapies available to an individual having cancer, a determination of the genetic factors that influence, for example, response to a particular drug, could be used to provide a patient with a personalized treatment regime. Such personalized treatment regimens offer the potential to maximize therapeutic benefit to the patient while minimizing related side effects that can be associated with alternative and less effective treatment regimens. SUMMARY OF THE INVENTION [008] According to a first aspect of the invention, methods for inhibiting the proliferation of cells that are MTAP-deficient and/or MTA-accumulating, including types of glioblastoma and other cancer cells, are provided. The methods comprise the step of administering, to a subject in need thereof, a PRMT5 inhibitor in an amount that is effective to inhibit the proliferation of the MTAP-deficient and/or MTA-accumulating cells, including cancer cells. In some embodiments, the MTAP-deficient and/or MTA-accumulating cells are also CDKN2A-deficient. Cells can be determined to be MTAP deficient by techniques known in the art, for example, immunohistochemistry utilizing an anti-MTAP 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 the sequence of MTAP provided in SEQ ID NO: 98, wherein the primer is no longer than about 30 nt, about 50 nt, or about 100 nt in length. Cells are determined to be MTA overproducing or MTA accumulating by techniques known in the art; methods for detecting MTA include, as a non-limiting example, liquid chromatography– electrospray ionization–tandem mass spectrometry (LC-ESI-MS/MS). [009] In one embodiment, the invention provides use of a molecule that inhibits the cellular function of the PRMT5 protein for the treatment of a disease associated with MTAP deficiency and/or MTA accumulation, including, but not limited to, a cancer, including, for example, but not limited to: glioblastoma, bladder cancer, pancreatic cancer, mesothelioma, melanoma, lung squamous, lung adenocarcinoma, diffuse large B-cell lymphoma, leukemia, head and neck cancer, and cancers of the kidney, breast, endometrium, urinary tract, liver, soft tissue, pleura and large intestine. [0010] 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 a disease associated with MTAP deficiency and/or MTA accumulation, including, but not limited to, a cancer, including, for example, but not limited to: glioblastoma, bladder cancer, pancreatic cancer, mesothelioma, melanoma, lung squamous, lung adenocarcinoma, diffuse large B-cell lymphoma, leukemia, head and neck cancer, and cancers of the kidney, breast, endometrium, urinary tract, liver, soft tissue, pleura and large intestine. [0011] 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. In some embodiments, the antibody or a derivative thereof binds to a HLA-peptide complex comprising a peptide having the sequence of any of SEQ ID NOs: 101-158. [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. [0015] According to one embodiment, the second therapeutic agent is an anti-cancer agent selected from the list consisting of: an 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, LEE011, and inhibitors of HDM2i, PI3K/mTOR-I, MAPKi, RTKi (EGFRi, FGFRi, METi, IGFiRi, JAKi, and WNTi. [0016] According to a second aspect of the invention, a method of determining if a subject afflicted with a cancer will respond to therapeutic treatment with a PRMT5 inhibitor is provided. The method comprises the steps: a) evaluating a test sample obtained from said subject for MTAP deficiency and/or MTA accumulation relative to a reference normal or non-cancerous control sample, wherein MTAP deficiency and/or MTA accumulation in the test sample indicates that the subject will respond to therapeutic treatment with a PRMT5 inhibitor; wherein the method comprises the following optional steps: b) determining the level 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 of PRMT5 in the subject following step c), wherein a decrease in the level of PRMT5 is correlated with the inhibition of the proliferation of the cancer, and wherein steps c) and d) are performed after steps a) and b).