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WO 2019/016772 A2 24 January 2019 (24.01.2019) W !P O PCT

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WO 2019/016772 A2 24 January 2019 (24.01.2019) W !P O PCT (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 2019/016772 A2 24 January 2019 (24.01.2019) W !P O PCT (51) International Patent Classification: (81) Designated States (unless otherwise indicated, for every A61K 38/00 (2006.01) C12N 15/113 (2010.01) kind of national protection available): AE, AG, AL, AM, C12N 9/14 (2006.01) G01N 33/50 (2006.01) 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, (21) International Application Number: DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, HN, PCT/IB20 18/0554 18 HR, HU, ID, IL, IN, IR, IS, JO, JP, KE, KG, KH, KN, KP, (22) International Filing Date: KR, KW, KZ, LA, LC, LK, LR, LS, LU, LY, MA, MD, ME, 20 July 2018 (20.07.2018) 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, (25) Filing Language: English SC, 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 62/535,539 2 1 July 2017 (21 .07.2017) US kind of regional protection available): ARIPO (BW, GH, GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, ST, SZ, TZ, (71) Applicant: NOVARTIS AG [CH/CH]; Lichtstrasse 35, UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, TJ, 4056 Basel (CH). TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, DK, (72) Inventors: BILLY, Eric; Novartis Pharma AG, Novartis EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, LV, Institutes for Biomed. Research, NIBR Klybeck, Postfach, MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, SM, 4002 Basel (CH). DEWECK, Antoine; Novartis Pharma TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, GW, AG, Novartis Institutes for Biomed. Research, NIBR Kly KM, ML, MR, NE, SN, TD, TG). beck, Postfach, 4002 Basel (CH). GOLJI, Javad; Novar tis Institutes for BioMedical Research, Inc., 250 Massa Declarations under Rule 4.17: chusetts Avenue, Cambridge, Massachusetts 02139 (US). — as to applicant's entitlement to applyfor and be granted a HOFFMAN, Gregory; Novartis Institutes for BioMedical patent (Rule 4.1 7(H)) Research, Inc., 500 Technology Square, Cambridge, Mass Published: achusetts 02139 (US). HOFMANN, Francesco; Novar — without international search report and to be republished tis Pharma AG, Novartis Institutes for Biomed. Research, upon receipt of that report (Rule 48.2(g)) NIBR Klybeck, Postfach, 4002 Basel (CH). KAUFF- — in black and white; the international application as filed MANN, Audrey; Novartis Pharma AG, Novartis Institutes contained color or greyscale and is availablefor download for Biomed. Research, NIBR Klybeck, Postfach, 4002 Basel from PATENTSCOPE (CH). MAVRAKIS, Konstantinos John; Novartis Insti tutes for BioMedical Research, Inc., 250 Massachusetts Av enue, Cambridge, Massachusetts 02139 (US). MCDON¬ ALD III, Earl Robert; Novartis Institutes for BioMed ical Research, Inc., 250 Massachusetts Avenue, Cambridge, Massachusetts 02139 (US). SELLERS, William; Novar tis Institutes for BioMedical Research, Inc., 250 Massa chusetts Avenue, Cambridge, Massachusetts 02139 (US). SCHMELZLE, Tobias; Novartis Pharma AG, Novartis In stitutes for Biomed. Research, NIBR Klybeck, Postfach, 4002 Basel (CH). STEGMEIER, Frank Peter; Novar tis Institutes for BioMedical Research, Inc., 250 Massa chusetts Avenue, Cambridge, Massachusetts 02139 (US). SCHLABACH JR., Michael Ray; Novartis Institutes for BioMedical Research, Inc., 250 Massachusetts Avenue, Cambridge, Massachusetts 02139 (US). (74) Agent: NOVARTIS AG; Lichtstrasse 35, 4056 Basel (CH). © (54) Title: COMPOSITIONS AND METHODS TO TREAT CANCER (57) Abstract: The disclosure provides novel personalized therapies, kits, transmittable forms of information and methods for use in o treating patients having cancer, wherein the cancer is amenable to therapeutic treatment with an inhibitor, e.g., an inhibitor of any of the targets disclosed herein. Kits, methods of screening for candidate inhibitors, and associated methods of treatment are also provided. COMPOSITIONS AND METHODS TO TREAT CANCER BACKGROUND Cancer is a leading cause of death in the world. Approximately 595,000 people per year die from cancer in the U. S . alone. The standard of care for many cancers includes surgery, radiotherapy, and/or cytotoxic chemotherapy, with few targeted agents currently approved. There is an increasing body of evidence suggesting that a patient's genetic profile can be indicative of 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 regimen. Currently, there are limited targeted therapies that have been approved for use in cancer. Therefore, there is an unmet need to develop targeted, personalized therapies for cancer. SUMMARY The present disclosure is based, at least in part, on the identification of targets associated with specific cancer types using a large-scale RNAi screen. These targets can include genes, e.g., oncogenes, presently identified to be associated with specific cancer types. In some embodiments, the targets were identified from a large-scale RNAi screen performed on 398 cancer cell lines. Accordingly, provided herein are, inter alia, methods and compositions comprising an inhibitor of one or more of the targets disclosed herein, e.g., an inhibitor of one or more of the targets disclosed in Tables 1 and 2 . These inhibitors can be used to treat cancers, e.g., hematological cancers or solid tumors, associated with the expression or activity of their corresponding cancer targets. Additionally disclosed are methods and compositions for identifying and/or evaluating a subject having a cancer, e.g., by detecting a genetic alteration, the level and/or activity of one or more of the targets disclosed herein. In one embodiment, the present disclosure also provides methods for treating selected patient populations with one or more of the inhibitors disclosed herein. In one embodiment, the patient population is selected on the basis of having a cancer associated with any one of the targets disclosed herein. Thus, therapeutic and diagnostic targets for the treatment of cancer are disclosed. Accordingly, in one aspect, the present disclosure provides a method for reducing, e.g., inhibiting, proliferation of cancer cells, e.g., hematological cancer cells or solid tumor cells. The methods may comprise administering to a subject in need thereof, an inhibitor, e.g., an inhibitor of any of the targets disclosed in Tables 1 or 2 , in an amount that is effective to reduce, e.g., inhibit, proliferation of the cancer cells. In an embodiment, the present disclosure provides an inhibitor, e.g., an inhibitor of any of the targets disclosed in Tables 1 or 2 , for use in the treatment of cancer, e.g., hematological cancers or solid tumors. Also provided is a use of the inhibitors for the manufacture of a medicament for treating cancer, such as hematological cancers or solid tumors or any cancers disclosed herein. In another aspect, the present disclosure provides a method of treating (e.g., inhibiting, reducing, ameliorating or preventing) a proliferative condition or disorder (e.g., a cancer) in a subject. The methods include administering to the subject an inhibitor (e.g., an inhibitor of any one of the targets disclosed in Tables 1 or 2), thereby treating the proliferative condition or disorder (e.g., the cancer). In some embodiments of any of the methods or uses disclosed herein, the method or use comprises administering to a subject in need thereof, an inhibitor of any of the targets disclosed in Tables 1 or 2 , in combination with a second therapeutic agent, e.g., 1, 2 , 3 , 4 or more therapeutic agents disclosed herein. In an embodiment, the second therapeutic agent is chosen from one or more of an anti-cancer agent, anti-allergic agents, anti-nausea agents (or anti-emetics), pain relievers, or cytoprotective agents, or a second therapeutic agent described herein. Methods of Evaluating, Selecting and Monitoring a Patient The disclosure also provides methods of evaluating, predicting, selecting, or monitoring, a subject who will receive, is about to receive, has received or is receiving a therapeutic treatment (e.g., a treatment with an inhibitor, e.g., an inhibitor of any of the targets disclosed in Tables 1 or 2). In another aspect, disclosed herein are methods of evaluating or predicting the responsiveness of a subject having a cancer (e.g., any of the cancers disclosed in Tables 1 or 2), to a therapeutic treatment (e.g., a treatment with an inhibitor, e.g., an inhibitor of any of the targets disclosed in Tables 1 or 2). The method comprises: evaluating the presence or absence of a genetic alteration (e.g., a genetic alteration as described in Table 2), e.g., gene amplification, copy number deletion, mutation or presence of microsatellites, wherein: (i) the presence of the alteration is indicative that the subject is likely to respond to the therapeutic treatment; or (ii) the absence of the alteration is indicative that the subject is less likely to respond to the therapeutic treatment; for at least one time point, e.g., prior to administration of the therapeutic treatment, thereby evaluating the subject, or predicting the responsiveness of the subject to a therapeutic treatment. In one embodiment, responsive to said evaluation or prediction, the method further comprises selecting the subject for administration in an amount effective to treat the cancer, an inhibitor (e.g., an inhibitor of any of the targets disclosed in Tables 1 or 2) to treat the cancer (e.g., any of the cancers disclosed in Tables 1 or 2) in the subject.
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