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Wo2017/132291 (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 W O 2017/132291 A l 3 August 2017 (03.08.2017) P O P C T (51) International Patent Classification: [US/US]; 77 Massachusetts Avenue, Cambridge, MA A61K 48/00 (2006.01) C12Q 1/68 (2006.01) 02139 (US). THE GENERAL HOSPITAL CORPORA¬ A61K 39/395 (2006.01) G01N 33/574 (2006.01) TION [US/US]; 55 Fruit Street, Boston, MA 021 14 (US). C12N 15/11 (2006.01) (72) Inventors; and (21) International Application Number: (71) Applicants : REGEV, Aviv [US/US]; 415 Main Street, PCT/US2017/014995 Cambridge, MA 02142 (US). BERNSTEIN, Bradley [US/US]; 55 Fruit Street, Boston, MA 021 14 (US). (22) International Filing Date: TIROSH, Itay [US/US]; 415 Main Street, Cambridge, 25 January 20 17 (25.01 .2017) MA 02142 (US). SUVA, Mario [US/US]; 55 Fruit Street, (25) Filing Language: English Bostn, MA 02144 (US). ROZENBALTT-ROSEN, Orit [US/US]; 415 Main Street, Cambridge, MA 02142 (US). (26) Publication Language: English (74) Agent: NIX, F., Brent; Johnson, Marcou & Isaacs, LLC, (30) Priority Data: 317A East Liberty St., Savannah, GA 31401 (US). 62/286,850 25 January 2016 (25.01.2016) US 62/437,558 2 1 December 201 6 (21. 12.2016) US (81) Designated States (unless otherwise indicated, for every kind of national protection available): AE, AG, AL, AM, (71) Applicants: THE BROAD INSTITUTE, INC. [US/US]; AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, 415 Main Street, Cambridge, MA 02142 (US). MAS¬ BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DJ, DK, DM, SACHUSETTS INSTITUTE O F TECHNOLOGY [Continued on nextpage] (54) Title: GENETIC, DEVELOPMENTAL AND MICRO-ENVIRONMENTAL PROGRAMS IN IDH-MUTANT GLIOMAS, COMPOSITIONS OF MATTER AND METHODS OF USE THEREOF (57) Abstract: This invention relates generally to compositions and methods for identifying genes and gene networks that respond to, mod ulate, control or otherwise influence tumors and tissues, including cells and cell types of the tumors and tissues, and malignant, microenviron- mental, or immunologic states of the tumor cells and tissues. The in H-mytant astrocytoma Row cytometry i vention also relates to methods of diagnosing, prognosing and/or sta ir r i atfe s ; grade ill or 96 pat is ging of tumors, tissues and cells, and provides compositions and meth FIG 1A ods of modulating expression of genes and gene networks of tumors, tissues and cells, as well as methods of identifying, designing and se lecting appropriate treatment regimens. FIG 1B-C < l lll II III, I ll FIG - o o WO 2017/132291 Al Illlll II lllll Hill Hill llll III III Hill lllll lllll lllll lllll III! llll i l llll DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, DK, EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, GT, HN, HR, HU, ID, IL, IN, IR, IS, JP, KE, KG, KH, LU, LV, MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, KN, KP, KR, KW, KZ, LA, LC, LK, LR, LS, LU, LY, SI, SK, SM, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, MA, MD, ME, MG, MK, MN, MW, MX, MY, MZ, NA, GN, GQ, GW, KM, ML, MR, NE, SN, TD, TG). NG, NI, NO, NZ, OM, PA, PE, PG, PH, PL, PT, QA, RO, Published: 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, — with international search report (Art. 21(3)) VN, ZA, ZM, ZW. — before the expiration of the time limit for amending the (84) Designated States (unless otherwise indicated, for even- claims and to be republished in the event of receipt of kind of regional protection available): ARIPO (BW, GH, amendments (Rule 48.2(h)) GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, ST, SZ, — with sequence listing part of description (Rule 5.2(a)) TZ, UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, TJ, TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, GENETIC, DEVELOPMENTAL AND MICRO-ENVIRONMENTAL PROGRAMS IN IDH-MUTANT GLIOMAS, COMPOSITIONS OF MATTER AND METHODS OF USE THEREOF RELATED APPLICATIONS AND INCORPORATION BY REFERENCE [0001] This application claims priority and benefit of U.S. provisional application Serial numbers 62/286,850, filed January 25, 2016 and 62/437,558, filed December 21, 2016. [0002] Reference is made to International Patent Application Serial No. PCT/US 16/400 15, filed June 29, 2016 and US Provisional Application Serial number. 62/186,227, filed June 29, 2015. The foregoing applications, and all documents cited therein or during their prosecution ("appln cited documents") and all documents cited or referenced in the appln cited documents, and all documents cited or referenced herein ("herein cited documents"), and all documents cited or referenced in herein cited documents, together with any manufacturer's instructions, descriptions, product specifications, and product sheets for any products mentioned herein or in any document incorporated by reference herein, are hereby incorporated herein by reference, and may be employed in the practice of the invention. More specifically, all referenced documents are incorporated by reference to the same extent as if each individual document was specifically and individually indicated to be incorporated by reference. STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH [0003] This invention was made with government support under grant numbers CA180922, CA14051 and CA165962 awarded by the National Institutes of Health. The government has certain rights in the invention. FIELD OF THE INVENTION [0004] The present invention generally relates to the methods of identifying and using gene expression profiles representative of malignant, microenvironmental, or immunologic states of tumors, and use of such profiles for diagnosing, prognosing and/or staging of gliomas and designing and selecting appropriate treatment regimens. BACKGROUND OF THE INVENTION [0005] Tumors are complex ecosystems defined by spatiotemporal interactions between heterogeneous cell types, including malignant, immune and stromal cells (1). Each tumor's cellular composition, as well as the interplay between these components, may exert critical roles in cancer development (2). However, the specific components, their salient biological functions, and the means by which they collectively define tumor behavior remain incompletely characterized. [0006] Tumor cellular diversity poses both challenges and opportunities for cancer therapy. This is most clearly demonstrated by the remarkable but varied clinical efficacy achieved in malignant melanoma with targeted therapies and immunotherapies. First, immune checkpoint inhibitors produce substantial clinical responses in some patients with metastatic melanomas (3-7); however, the genomic and molecular determinants of response to these agents remain poorly understood. Although tumor neoantigens and PD-L1 expression clearly contribute (8-10), it is likely that other factors from subsets of malignant cells, the microenvironment, and tumor-infiltrating lymphocytes (TILs) also play essential roles ( 11). Second, melanomas that harbor the BRAFV600E mutation are commonly treated with RAF/MEK -inhibition prior to or following immune checkpoint inhibition. Although this regimen improves survival, virtually all patients eventually develop resistance to these drugs (12,13). Unfortunately, no targeted therapy currently exists for patients whose tumors lack BRAF mutations —including NRAS mutant tumors, those with inactivating NF1 mutations, or rarer events {e.g., RAF fusions). Collectively, these factors highlight the need for a deeper understanding of melanoma composition and its impact on clinical course. [0007] The next wave of therapeutic advances in cancer will likely be accelerated by emerging technologies that systematically assess the malignant, microenvironmental, and immunologic states most likely to inform treatment response and resistance. An ideal approach would assess salient cellular heterogeneity by quantifying variation in oncogenic signaling pathways, drug-resistant tumor cell subsets, and the spectrum of immune, stromal and other cell states that may inform immunotherapy response. Toward this end, emerging single-cell genomic approaches enable detailed evaluation of genetic and transcriptional features present in lOOs-lOOOs of individual cells per tumor (14-16). In principle, this approach may provide a comprehensive means to identify all major cellular components simultaneously, determine their individual genomic and molecular states (15), and ascertain which of these features may predict or explain clinical responses to anticancer agents. [0008] Intra-tumoral heterogeneity contributes to therapy failure and disease progression in cancer. Tumor cells vary in proliferation, sternness, invasion, apoptosis, chemoresistance and metabolism (72). Various factors may contribute to this heterogeneity. On the one hand, in the genetic model of cancer, distinct tumor subclones are generated by branched genetic evolution of cancer cells; on the other hand, it is also becoming increasingly clear that certain cancers display diversity due to features of normal tissue organization. From this perspective, non-genetic determinants, related to developmental pathways and epigenetic programs, such as those associated with the self-renewal of tissue stem cells and their differentiation into specialized cell types, contribute to tumor functional heterogeneity (73,74). In particular, in a hierarchical developmental model of cancer, cancer stem cells (CSC) have the unique capacity to self-renew and to generate non-tumorigenic differentiated cancer cells. This model is still controversial, but - if correct - has important practical implications for patient management (75,76). Pioneering studies in leukemias have indeed demonstrated that targeting stem cell programs or triggering cellular differentiation can override genetic alterations and yield clinical benefit (72,77). [0009] Relating the genetic and non-genetic models of cancer heterogeneity, especially in solid human tumors, has been limited due to technical challenges. Analysis of human tumor genomes has shed light on the genetic model, but is typically performed in bulk and does not inform us on the concomitant functional states of cancer cells.
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