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WO 2018/183580 Al 04 October 2018 (04.10.2018) W !P O PCT

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WO 2018/183580 Al 04 October 2018 (04.10.2018) W !P O PCT (12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization I International Bureau (10) International Publication Number (43) International Publication Date WO 2018/183580 Al 04 October 2018 (04.10.2018) W !P O PCT (51) International Patent Classification: TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, GW, A61K 35/14 (2006.01) A61K 47/48 (2006.01) KM, ML, MR, NE, SN, TD, TG). A61K 39/00 (2006.01) Published: (21) International Application Number: — with international search report (Art. 21(3)) PCT/US20 18/024970 — before the expiration of the time limit for amending the (22) International Filing Date: claims and to be republished in the event of receipt of 28 March 2018 (28.03.2018) amendments (Rule 48.2(h)) (25) Filing Language: English (26) Publication Language: English (30) Priority Data: 62/478,380 29 March 2017 (29.03.2017) US (71) Applicants: THE BROAD INSTITUTE, INC [US/US]; 415 MAIN STREET, Cambridge, Massachusetts 02142 (US). DANA-FARBER CANCER INSTITUTE, INC. [US/US]; Office of General Counsel BP 372A, 450 Brook- line Ave., Boston, Massachusetts 02215 (US). (72) Inventors: GOLDSTEIN, Jonathan; c/o THE BROAD INSTITUTE, INC., 415 MAIN STREET, Cam bridge, Massachusetts 02142 (US). MEYERSON, Matthew; c/o DANA-FARBER CANCER INSTI TUTE, INC., 450 BROOKLINE AVENUE, GENERAL COUNSEL BP372A, Boston, Massachusetts 02215 (US). STRATHDEE, Craig; c/o THE BROAD INSTITUTE, INC., 415 MAIN STREET, Cambridge, Massachusetts 02142 (US). (74) Agent: EMMONS, Richard et al. ; Burns & Levinson LLP, 125 Summer Street, Boston, Massachusetts 021 10 (US). (81) Designated States (unless otherwise indicated, for every kind of national protection available): AE, AG, AL, AM, AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DJ, DK, DM, DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, HN, HR, HU, ID, IL, IN, IR, IS, JO, JP, KE, KG, KH, KN, KP, KR, KW, KZ, LA, LC, LK, LR, LS, LU, LY, MA, MD, ME, MG, 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, 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. (84) Designated States (unless otherwise indicated, for every kind of regional protection available): ARIPO (BW, GH, GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, ST, SZ, TZ, UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, TJ, TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, DK, o EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, LV, 00 MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, SM, (54) Title: COMPOSITIONS AND METHODS FOR TREATMENT OF PEROXISOME PROLIFERATOR-ACTIVATED RECEP oo TOR GAMMA (PPARG) ACTIVATED CANCER © (57) Abstract: The present disclosure provides compositions and methods for the treatment of PPARG activated cancer. For example, the present disclosure provides PPARG signaling modulators for the treatment of bladder cancer. In particular, therapeutic and/or prophylactic compositions and uses of PPARG inverse-agonists are described. COMPOSITIONS AND METHODS FOR TREATMENT OF PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR GAMMA (PPARG) ACTIVATED CANCER CROSS-REFERENCE TO RELATED APPLICATION This application claims the benefit of priority of U.S. Provisional Application No. 62/478,380, filed March 29, 2017, the entire contents of which are hereby incorporated by reference. STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH This invention was made with government support under Grant No. 5R35CA197568, awarded by the National Institutes of Health. The government has certain rights in the invention. FIELD OF THE DISCLOSURE The present disclosure provides compositions and methods for the treatment of Peroxisome proliferator-activated receptor gamma (PPARG) activated cancer. More particularly, the present disclosure provides inverse-agonists of PPARG activated cancer for the treatment of breast cancer, esophageal cancer, pancreatic cancer, colorectal cancer, hepatocellular cancer, and bladder cancer. BACKGROUND OF THE DISCLOSURE It is estimated that approximately 7.5 million people worldwide die from cancer every year. Peroxisome proliferator-activated receptor gamma (PPARG) activated cancers (e.g., breast cancer, esophageal cancer, pancreatic cancer, colorectal cancer, hepatocellular cancer, bladder cancer, and the like) represent a significant class of cancers. For example, bladder cancer is the fifth most commonly diagnosed cancer type in the United States. About half of all bladder cancer patients are diagnosed with non-invasive/superficial urothelial carcinoma of the bladder and respond well to existing chemotherapy regimens, with a 5-year survival rate of 96%. Patients diagnosed with invasive disease have a poorer prognosis, with a 5-year survival rate of 70% or less, depending upon extent of invasion beyond the bladder. Currently, there are no FDA- approved targeted therapeutics available to these patients. Accordingly, there is an urgent need for compositions and methods for treating PPARG activated cancers such as bladder cancer. SUMMARY OF THE DISCLOSURE The present disclosure relates, at least in part, to the discovery of Peroxisome proliferator- activated receptor gamma (PPARG) signaling as a therapeutic target for the treatment of various PPARG activated cancers such as, for example, breast cancer, esophageal cancer, pancreatic cancer, colorectal cancer, hepatocellular cancer, and bladder cancer. As described herein, the present disclosure provides PPARG signaling modulators (e.g., inverse-agonists) that are able to down regulate PPARG signaling in PPARG activated cancers, thereby decreasing cellular proliferation associated with PPARG activated cancers (e.g., breast cancer, esophageal cancer, pancreatic cancer, colorectal cancer, hepatocellular cancer, bladder cancer, and the like). It is also contemplated within the scope of the disclosure that molecular genetic methodologies (e.g., CRISPR/Cas, RNAi, and the like) that allow editing of gene sequences and mutations that provoke PPARG activated cancers can also be used as therapeutic modalities to down regulate PPARG signaling in PPARG activated cancers, thereby blocking the increased cellular proliferation associated with PPARG activated cancers. In particular, the present disclosure provides inverse-agonists that are able to reverse up-regulation of PPARG signaling in PPARG activated cancers, thereby providing a therapeutic modality capable of treating PPARG activated cancers such as, for example, bladder cancer. In an aspect, the present disclosure provides a method of treating a subject having a peroxisome proliferator-activated receptor gamma (PPARG) activated cancer that includes a step of administering a therapeutically effective amount of a PPARG signaling modulator to the subject. In an embodiment, the PPARG signaling modulator is an antagonist or an inverse-agonist of PPARG signaling. In an embodiment, the PPARG signaling modulator is an inverse-agonist of PPARG signaling. In an embodiment, the inverse-agonist is selected from the group consisting of T0070907, T0070907 analogs, SRI 0221, SRI 0221 analogs, and combinations thereof. In an embodiment, the PPARG activated cancer is associated with a mutation in PPARG and/or retinoid X receptor alpha (RXRA). In an embodiment, the mutation in PPARG is T447M, PPARG focal gene amplification, or a PPARG missense mutation. In an embodiment, the mutation in RXRA is S427F/Y. In an embodiment, the PPARG activated cancer is associated with an up-regulated peroxisome proliferator-activated receptor (PPAR) signaling pathway. In an embodiment, the up- regulated PPAR signaling pathway is associated with increased expression of one or more genes selected from the group consisting of Uroplakin 1A (UPK1A), Uroplakin IB (UPK1B), Uroplakin (UPK2), Keratin 20 (KRT20), GATA Binding Protein 3 (GATA3), Nuclear Receptor Corepressor 1 (NCORl), Nuclear Receptor Corepressor 2 (NCOR2), Fatty Acid Binding Protein 4 (FABP4), Forkhead Box Al (FOXA1), CD36 Molecule (CD36), Acyl-CoA Oxidase 1 (ACOX1), 3-Hydroxy-3-Methylglutaryl-CoA Synthase 2 (HMGCS2), Acyl-CoA Synthetase Long-Chain Family Member 5 (ACSL5), Arachidonate 5-Lipoxygenase (ALOX5), and Acyl- CoA Synthetase Long-Chain Family Member 1 (ACSL1). In an embodiment, the PPARG activated cancer is breast cancer, esophageal cancer, pancreatic cancer, colorectal cancer, hepatocellular cancer, or bladder cancer. In an embodiment, the bladder cancer is luminal or non-luminal bladder cancer, basal bladder cancer, muscle-invasive bladder cancer, or non-muscle-invasive bladder cancer. In an embodiment, the step of administering the inverse-agonist to the subject decreases proliferation of one or more PPARG activated cancer cells within the subject. The subject may be a human or non-human mammal (e.g., a bovine, a canine, an equine, a feline, an ovine, a primate, and the like). In an embodiment, the PPARG signaling modulator is a CRISPR-Cas system, optionally a CRISPR-Cas system that replaces a T447M mutation in PPARG, a focal gene amplification of PPARG, a CRISPR-Cas system that replaces a S427F/Y mutation in RXRA, or any combination thereof. In an embodiment, the PPARG signaling modulator is an inhibitory nucleic acid, optionally an antisense oligonucleotide or RNAi agent. In an aspect, the present disclosure provides a method of treating a subject diagnosed with a peroxisome proliferator-activated receptor gamma (PPARG) activated cancer that includes the steps of: performing an assay to determine the identity of an amino acid at position 447 of PPARG and/or position 427 of retinoid X receptor alpha (RXRA), wherein a PPARG reference amino acid at position 447 is threonine (T) and a RXRA reference amino acid at position 427 is serine (S); detecting the presence of a PPARG amino acid variation relative to the PPARG reference amino acid, wherein the PPARG amino acid variation is methionine (M) and/or a RXRA amino acid variation relative to the RXRA reference amino acid, where the RXRA amino acid variation is phenylalanine (F) or tyrosine (Y); and administering a therapeutically effective amount of a PPARG signaling modulator to the subject having a PPARG T447M variation and/or a RXRA S427F/Y variation.
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