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WO 2019/094955 Al 16 May 2019 (16.05.2019) W 1P O PCT

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WO 2019/094955 Al 16 May 2019 (16.05.2019) W 1P 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 2019/094955 Al 16 May 2019 (16.05.2019) W 1P O PCT (51) International Patent Classification: (74) Agent: SCHER, Michael B. et al.; Johnson, Marcou & A61K 39/395 (2006.01) C07K 14/705 (2006.01) Isaacs, LLC, P.O. Bo 691, Hoschton, Georgia 30548 (US). A61K 47/68 (2017.01) C07K 16/28 (2006.01) (81) Designated States (unless otherwise indicated, for every A61P 35/00 (2006.01) C07K 16/32 (2006.01) kind of national protection available): AE, AG, AL, AM, (21) International Application Number: AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, BZ, PCT/US20 18/060799 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, (22) International Filing Date: HR, HU, ID, IL, IN, IR, IS, JO, JP, KE, KG, KH, KN, KP, 13 November 2018 (13. 11.2018) KR, KW, KZ, LA, LC, LK, LR, LS, LU, LY, MA, MD, ME, (25) Filing Language: English 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, (26) Publication Language: English SC, SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, (30) Priority Data: TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. 62/585,468 13 November 2017 (13. 11.2017) US (84) Designated States (unless otherwise indicated, for every 62/586,093 14 November 2017 (14. 11.2017) US kind of regional protection available): ARIPO (BW, GH, (71) Applicants: THE BROAD INSTITUTE, INC. [US/US]; GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, ST, SZ, TZ, 415 Main Street, Cambridge, Massachusetts 02142 (US). UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, TJ, MASSACHUSETTS INSTITUTE OF TECHNOLO¬ TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, DK, GY [US/US]; 77 Massachusetts Avenue, Cambridge, EE, ES, FI, FR, GB, GR, HR, HU, ΓΕ , IS, IT, LT, LU, LV, Massachusetts 02139 (US). THE GENERAL HOSPI¬ MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, SM, TAL CORPORATION [US/US]; 55 Fruit Street, Boston, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, GW, Massachusetts 021 14 (US). DANA-FARBER CANCER KM, ML, MR, NE, SN, TD, TG). INSTITUTE, INC. [US/US]; 450 Brookline Avenue, Boston, MA 02215 (US). Published: — with international search report (Art. 21(3)) (72) Inventors; and — with sequence listing part of description (Rule 5.2(a)) (71) Applicants: BERNSTEIN, Bradley [US/US]; c/o 55 Fruit Street, Boston, Massachusetts 021 14 (US). FILBIN, Mariella [US/US]; c/o 415 Main Street, Cambridge, Mass¬ achusetts 02142 (US). TIROSH, Itay [US/US]; c/o 415 Main Street, Cambridge, Massachusetts 02142 (US). HOV- ESTADT, Volker [US/US]; c/o 55 Fruit Street, Boston, Massachusetts 021 14 (US). (72) Inventors: SUVA, Mario; c/o 55 Fruit Street, Boston, Massachusetts 021 14 (US). REGEV, Aviv; c/o 415 Main Street, Cambridge, Massachusetts 02142 (US). (54) Title: METHODS AND COMPOSITIONS FOR TARGETING DEVELOPMENTAL AND ONCOGENIC PROGRAMS IN H3K27M GLIOMAS © FIG. IB (57) Abstract: The subject matter disclosed herein is generally directed to compositions and methods for treating diffuse gliomas with histone H3 lysine27-to-methionine mutations (H3K27M-gliomas). Disclosed herein are gene signatures specific for tumor cell types and compositions for treatment of H3K27M gliomas. In one embodiment, PRC 1 is targeted in a treatment regimen for H3K27M-gliomas. METHODS AND COMPOSITIONS FOR TARGETING DEVELOPMENTAL AND ONCOGENIC PROGRAMS IN H3K27M GLIOMAS CROSS-REFERENCE TO RELATED APPLICATIONS [0001] This application claims the benefit of U.S. Provisional Application Nos. 62/585,468, filed November 13, 2017 and 62/586,093, filed November 14, 2017. The entire contents of the above-identified applications are hereby fully incorporated herein by reference. STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH [0002] This invention was made with government support under grant Nos. CA1 80922, CA202820, CA14051, CA216873, CA165962, CA090354 and CA142536 awarded by the National Institutes of Health. The government has certain rights in the invention. TECHNICAL FIELD [0003] The subject matter disclosed herein is generally directed to compositions and methods for treating diffuse gliomas with histone H3 lysine27-to-methionine mutations (H3K27M- gliomas). REFERENCE TO AN ELECTRONIC SEQUENCE LISTING [0004] The contents of the electronic sequence listing (BROD_2296WP_ST25.txt"; Size is 10 Kilobytes and it was created on November 2, 2018) is herein incorporated by reference in its entirety. BACKGROUND [0005] Pediatric malignancies arise at specific time points and locations during development and only harbor a limited set of genomic aberrations compared to their adult counterparts (7). This pattern is thought to result from the precise interplay between transforming genetic events and susceptible cellular contexts that expand at specific times during development. Deciphering both lineage-defined and somatically altered cellular states and gene regulatory programs in patient tumors thus has broad implications for pediatric oncology. [0006] Diffuse midline gliomas with histone H3 lysine27-to-methionine mutations (H3K27M-gliomas), including diffuse intrinsic pontine glioma (DIPG), thalamic glioma and spinal cord glioma, are aggressive pediatric cancers that are uniformly fatal despite multimodal treatment strategies. These tumors are defined by a somatic mutation in H3F3A or HISTH3B/C, leading to K27M mutation in histone H3.3 or H3.1, respectively (2-5). H3K27M-gliomas are both spatially and temporally restricted: spatially, they are exclusive to midline structures of the brain (thalamus, pons, spinal cord); temporally, they occur primarily in young children. The occurrence of these tumors in precise anatomic locations and age groups suggests that a particular cell type, potentially undergoing rapid expansion at that time, is susceptible to transformation by H3K27M. [0007] Consistently, experimental models have suggested that neural precursor cells ( PC) derived from iPS cells - but not more differentiated cell types - can be transformed in vitro by H3K27M in combination with TP53 mutation and PDGFRA overexpression, alterations frequently observed in midline gliomas (6). The transforming effect of H3K27M is thought to result from the ability of the mutant histone to suppress EZH2, the catalytic subunit of Polycomb Repressive Complex 2 (PRC2), and thereby compromise epigenetic repression (7-10). Transformation of neural precursors by H3K27M has been proposed to reset them into a more primitive stem cell state and to result in a differentiation block (6). While this model is experimentally supported in vitro, very little is known about its relevance in vivo, and more generally about the cellular composition of H3K27M-gliomas in patients, i.e. the stem and differentiated cells they harbor, and how specific cell types, developmental cell states and genetic events cooperate. [0008] Single-cell RNA-sequencing (scRNA-seq) of human tumors can help address these questions through characterization of cancer cell states, their proliferative signatures and their similarity to normal or other malignant cell types. Furthermore, it is also possible to identify genetic aberrations in these same cells, either by computationally inferring chromosomal aberrations (11-15), or, when using full-length scRNA-seq (16), by detecting mutations in expressed transcripts, albeit with limited sensitivity (14). This strategy makes it possible to relate the genetic and epigenetic architecture of human malignancies at cellular resolution. In particular, Applicants recent studies indicate that adult IDH-mutant gliomas are driven by specific subpopulations of proliferative tumor cells with neural precursor cell-like (NPC-like) programs and capacity for differentiation (14, 15). However, it is currently unknown if these observations generalize to other classes of human gliomas, especially pediatric glioma, or if genetically-defined glioma subtypes display different cellular architectures and putative stem cell programs, as would be suggested by their distinct genotypes, age groups and anatomic locations. Notably, scRNA-seq in H3K27M-gliomas poses particular logistical hurdles compared to earlier studies in other tumor types (12-15), due to the rarity of this tumor, and the fact that only needle biopsies with minute pieces of tissue are sampled from the patients. Thus, there is a need to understand pathways and drivers involved in pediatric gliomas. SUMMARY [0009] In certain example embodiments, the present invention provides therapeutic targets and strategies for treating pediatric gliomas. Diffuse gliomas with histone H3 lysine27-to- methionine mutations (H3K27M-gliomas) arise nearly exclusively in the midline of the central nervous system, with peak incidence in young children, suggesting that tumorigenesis involves a cooperation between genetic factors and specific cellular contexts that arise during development. While the genetics of H3K27M-gliomas have been well-characterized, their cellular architecture remains uncharted. Here, Applicants performed single-cell RNA-sequencing (scRNA-seq) in 3,321 cells from six primary H3K27M-gliomas and matched cellular and xenograft models. Applicants found that H3K27M-gliomas exhibit unique oncogenic and developmental signatures, distinct from IDH-wildtype glioblastoma and IDH-mutant gliomas. H3K27M-gliomas are primarily composed of cells resembling oligodendrocyte precursor cells (OPC-like), while
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