This UOl application brings together three Principal Investigators (Drs. Orkin, Armstrong, and Roberts) to exploit genetically engineered mouse models of devastating human pediatric cancers for the development of new therapeutic avenues. A common theme in these projects is understanding the role of epigenetics in cancer initiation and/or progression. In Project 1, "New approaches to osteosarcoma", the involvement of the polycomb repressive complex PRC2, which is overactive in many malignancies as well as in the mouse model of osteosarcoma, will be addressed by a multidisciplinary and integrated biochemical and genetic strategies. In parallel, efforts will be directed toward high-throughput screens to identify agents that induce differentiation of osteosarcoma cells or selectively kill cells deficient in both p53 and Rb (as in the case of this cancer). Project 2, "Epigenetic programs in leukemia development and drug response", will focus on the roles of DNA methylation and PRC2 in leukemias due to translocations involving the MLL locus. In addition, efforts will concentrate on high-throughput screening to identify inhibitors of D0T1L, the H3K79 histone methyltransferase associated with MLL-fusion proteins. Project 3, "Epigenetics in cancer initiation and progression: from mechanism to therapy", focuses on malignancies due to SNF5 inactivation, as these appear to be "epigenetically driven" and without evident somatic mutations. The interactions between SNF5 and MLL or PRC2 will be tested genetically, and thereafter drugs that target epigenetic pathways will be tested for efficacy in SNF5-deficinet cancer in the mouse. This U01 program is highly integrated as the mouse models affecting epigenetic pathways are shared among the projects. In addition to providing a highly interactive framework, this integration will allow for identification of features that are either common or specific for these malignancies.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project--Cooperative Agreements (U01)
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Study Section
Special Emphasis Panel (ZCA1-SRLB-Q (M1))
Program Officer
Marks, Cheryl L
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Dana-Farber Cancer Institute
United States
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Wang, Xiaofeng; Roberts, Charles W M (2014) CARMA: CARM1 methylation of SWI/SNF in breast cancer. Cancer Cell 25:3-4
Helming, Katherine C; Wang, Xiaofeng; Roberts, Charles W M (2014) Vulnerabilities of mutant SWI/SNF complexes in cancer. Cancer Cell 26:309-17
Kim, Kimberly H; Roberts, Charles W M (2014) Mechanisms by which SMARCB1 loss drives rhabdoid tumor growth. Cancer Genet 207:365-72
Wang, Xiaofeng; Haswell, Jeffrey R; Roberts, Charles W M (2014) Molecular pathways: SWI/SNF (BAF) complexes are frequently mutated in cancer--mechanisms and potential therapeutic insights. Clin Cancer Res 20:21-7
Helming, Katherine C; Wang, Xiaofeng; Wilson, Boris G et al. (2014) ARID1B is a specific vulnerability in ARID1A-mutant cancers. Nat Med 20:251-4
Xie, Huafeng; Xu, Jian; Hsu, Jessie H et al. (2014) Polycomb repressive complex 2 regulates normal hematopoietic stem cell function in a developmental-stage-specific manner. Cell Stem Cell 14:68-80
Chen, L; Deshpande, A J; Banka, D et al. (2013) Abrogation of MLL-AF10 and CALM-AF10-mediated transformation through genetic inactivation or pharmacological inhibition of the H3K79 methyltransferase Dot1l. Leukemia 27:813-22
Baena, Esther; Shao, Zhen; Linn, Douglas E et al. (2013) ETV1 directs androgen metabolism and confers aggressive prostate cancer in targeted mice and patients. Genes Dev 27:683-98
Kim, Woojin; Bird, Gregory H; Neff, Tobias et al. (2013) Targeted disruption of the EZH2-EED complex inhibits EZH2-dependent cancer. Nat Chem Biol 9:643-50
Neff, Tobias; Armstrong, Scott A (2013) Recent progress toward epigenetic therapies: the example of mixed lineage leukemia. Blood 121:4847-53

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