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WO 2017/035116 Al O (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 2017/035116 Al 2 March 2017 (02.03.2017) P O P C T (51) International Patent Classification: DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, A61P 35/00 (2006.01) C12N 15/113 (2010.01) HN, HR, HU, ID, IL, IN, IR, IS, JP, KE, KG, KN, KP, KR, A61P 35/02 (2006.01) C12Q 1/68 (2006.01) KZ, LA, LC, LK, LR, LS, LU, LY, MA, MD, ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, OM, (21) International Application Number: PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SA, SC, PCT/US20 16/048 133 SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, (22) International Filing Date: TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. 23 August 2016 (23.08.2016) (84) Designated States (unless otherwise indicated, for every (25) Filing Language: English kind of regional protection available): ARIPO (BW, GH, GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, ST, SZ, (26) Publication Language: English TZ, UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, (30) Priority Data: TJ, TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, 62/209,682 25 August 2015 (25.08.2015) U S DK, EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, LV, MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, (71) Applicant: PRESIDENT AND FELLOWS OF HAR¬ SM, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, VARD COLLEGE [US/US]; 17 Quincy St., Cambridge, GW, KM, ML, MR, NE, SN, TD, TG). Massachusetts 02138 (US). Declarations under Rule 4.17 : (72) Inventors: GUJRAL, Taran; 33 Pond Rd., Brookline, — as to applicant's entitlement to apply for and be granted a Massachusetts 02445 (US). KIRSCHNER, Marc W.; 20 patent (Rule 4.1 7(H)) Gralynn Rd., Newton, Massachusetts 02459 (US). — as to the applicant's entitlement to claim the priority of the (74) Agents: RESNICK, David S. et al; Nixon Peabody LLP, earlier application (Rule 4.1 7(in)) 100 Summer St., Boston, Massachusetts 021 10-213 1 (US). Published: (81) Designated States (unless otherwise indicated, for every kind of national protection available): AE, AG, AL, AM, — with international search report (Art. 21(3)) AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, — with sequence listing part of description (Rule 5.2(a)) BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, (54) Title: METHODS AND COMPOSITIONS RELATING TO THE DIAGNOSIS AND TREATMENT OF CANCER FIG. 17 P c 2-G Hilifitaiiisi r v i · · ° < i g EC §g activation sensitizes ceils to 15 cytotoxic drugs Most are Ineffective in parental a c92 cells o (57) Abstract: Described herein are methods and compositions relating to the treatment of cancer, e.g., methods which account for a © subject's Hippo pathway activity/mutational status or which relate to combination treatments that influence the subject's Hippo path- way activity in order to enhance the effectiveness of chemo therapeutics. METHODS AND COMPOSITIONS RELATING TO THE DIAGNOSIS AND TREATMENT OF CANCER CROSS-REFERENCE TO RELATED APPLICATIONS [0001] This application claims benefit under 35 U.S.C. § 119(e) of U.S. Provisional Application No. 62/209,682 filed August 25, 2015, the contents of which are incorporated herein by reference in their entirety. GOVERNMENT SUPPORT [0002] This invention was made with government support under Grant Nos. ROI 152189 and R01 HD073 104 awarded by the National Institutes of Health. The U.S. government has certain rights in the invention. SEQUENCE LISTING [0003] The instant application contains a Sequence Listing which has been submitted electronically in ASCII format and is hereby incorporated by reference in its entirety. Said ASCII copy, created on August 22, 2016, is named 002806-085541-PCT_SL.txt and is 134,539 bytes in size. TECHNICAL FIELD [0004] The technology described herein relates to methods of diagnosing, prognosing, and treating cancer. BACKGROUND [0005] Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal forms of cancer. The 1- and 5-year survival rates for PDAC are about 10% and 4.6%, respectively, which are the lowest survival rates of all major cancers. Currently, the nucleoside analogue gemcitabine is the first line treatment of locally advanced and metastatic pancreatic cancer. However, most patients (>75%) treated with gemcitabine do not have an objective response to treatment and only a minority obtains stabilization of disease or partial response. SUMMARY [0006] As described herein, the inventors have discovered that cancer cells develop resistance to certain chemotherapeutics (e.g. gemcitabine) as the cell density increases. This developed resistance is controlled by alterations in the Hippo-YAP signaling pathway. The sensitivity of the cells to the chemotherapeutics can be restored by suppressing the Hippo-YAP pathway. This discovery permits both improved methods of treatment by 1) administering gemcitabine only to subjects who are sensitive to it, and 2) by inducing gemcitabine sensitivity by administering Hippo-YAP signaling inhibitors. [0007] In one aspect, described herein is a method of treating cancer, the method comprising administering a chemotherapeutic selected from the group consisting of: an antimetabolite; a nucleoside analog; an antifolate; a topoisomerase I inhibitor; a topoisomerase II inhibitor; an anthracycline; a tubulin modulator; a DNA cross-linking agent; a Src family kinase inhibitor; and a BCR-Abl kinase inhibitor; to a subject having cancer cells determined to have: a. a deletion, a truncation or inactivating mutation in FAT4; LATS 1; LATS2; STK1 1; or NF2; b. decreased expression of FAT4; LATS1; LATS2; STK11; or F2 relative to a reference; c. increased expression of YAP; CTGF; AREG; AMOTL2; AXL; or BIRC5 relative to a reference; d. decreased phosphorylation of YAP relative to a reference; or e. increased nuclear localization of YAP relative to a reference. In one aspect, provided herein is a therapeutically effective amount of a chemotherapeutic selected from the group consisting of: an antimetabolite; a nucleoside analog; an antifolate; a topoisomerase I inhibitor; a topoisomerase II inhibitor; an anthracycline; a tubulin modulator; a DNA cross-linking agent; a Src family kinase inhibitor; and a BCR-Abl kinase inhibitor; for use in a method of treating cancer, the method comprising administering the cytotoxic chemotherapeutic to a subject having cancer cells determined to have: a. a deletion, a truncation or inactivating mutation in FAT4; LATS1; LATS2; STK1 1; or NF2; b. decreased expression of FAT4; LATS1; LATS2; STK11; or F2 relative to a reference; c. increased expression of YAP; CTGF; AREG; AMOTL2; AXL; or BIRC5 relative to a reference; d. decreased phosphorylation of YAP relative to a reference; or e. increased nuclear localization of YAP relative to a reference. In some embodiments, the antimetabolite or nucleoside analog is selected from the group consisting of: gemcitabine; 5-FU; cladribine; cytarabine; tioguanine; mercaptopurine; and clofarabine. In some embodiments, the antifolate is methotrexate. In some embodiments, the topoisomerase I inhibitor is camptothecin, topotecan, or irrenotecan. In some embodiments, the topoisomerase II inhibitor is selected from the group consisting of: epirubicin; daunorubicin; doxorubicin; valrubicin; teniposide; etopiside; and mitoxantrone. In some embodiments the anthracycline is selected from the group consisting of: epirubicin; daunorubicin; doxorubicin; and valrubicin. In some embodiments, the tubulin modulator is ixabepilone. In some embodiments, the Src family kinase inhibitor or BCR-Abl kinase inhibitor is imatinib. In some embodiments, the DNA cross-linking agent is mitomycin. [0008] In one aspect, provided herein is a method of treating cancer, the method comprising administering a chemotherapeutic selected from the group consisting of: an antimetabolite; an anthracylcine; an anthracycline topoisomerase II inhibitor; a proteasome inhibitor; an mTOR inhibitor; an RNA synthesis inhibitor; a peptide synthesis inhibitor; an alkylating agent; an antiandrogen; a Src family kinase inhibitor; a BCR-Abl kinase inhibitor; a MEK inhibitor; and a kinase inhibitor; to a subject having cancer cells determined not to have: a. a deletion, a truncation, or inactivating mutation in FAT4; LATS1; LATS2; STK1 1; or NF2; b. decreased expression of FAT4; LATS1; LATS2; STK11; or F2 relative to a reference; c. increased expression of YAP; CTGF; AREG; AMOTL2; AXL; or BIRC5 relative to a reference; d. decreased phosphorylation of YAP relative to a reference; or e. increased nuclear localization of YAP relative to a reference. In one aspect, provided herein is a therapeutically effective amount of a compound selected from the group consisting of: an antimetabolite; an anthracylcine; an anthracycline topoisomerase II inhibitor; a proteasome inhibitor; an mTOR inhibitor; an RNA synthesis inhibitor; a peptide synthesis inhibitor; an alkylating agent; an antiandrogen; a Src family kinase inhibitor; a BCR-Abl kinase inhibitor; a MEK inhibitor; and a kinase inhibitor; for use in a method of treating cancer, the method comprising administering the compound to a subject having cancer cells determined not to have: a. a deletion, a truncation, or inactivating mutation in FAT4; LATS1; LATS2; STK1 1; or NF2; b. decreased expression of FAT4; LATS1; LATS2; STK11; or F2 relative to a reference; c. increased expression of YAP; CTGF; AREG; AMOTL2; AXL; or BIRC5 relative to a reference; d. decreased phosphorylation of YAP relative to a reference; or e. increased nuclear localization of YAP relative to a reference. In some embodiments, the anthracycline toposisomerase II inhibitor is selected from the group consisting of: daunorubicin; doxorubicin; epirubicin; and valrubicin. In some embodiments, the anthracycline is selected from the group consisting of: daunorubicin; doxorubicin; epirubicin; and valrubicin. In some embodiments, the proteasome inhibitor is carfilzomib or bortezomib.
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