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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project--Cooperative Agreements (U01)
Project #
5U01CA105423-10
Application #
8519311
Study Section
Special Emphasis Panel (ZCA1-SRLB-Q (M1))
Program Officer
Marks, Cheryl L
Project Start
2004-09-10
Project End
2014-07-31
Budget Start
2013-08-01
Budget End
2014-07-31
Support Year
10
Fiscal Year
2013
Total Cost
$728,812
Indirect Cost
$135,568
Name
Dana-Farber Cancer Institute
Department
Type
DUNS #
076580745
City
Boston
State
MA
Country
United States
Zip Code
02215
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Zhu, Nan; Chen, Mo; Eng, Rowena et al. (2016) MLL-AF9- and HOXA9-mediated acute myeloid leukemia stem cell self-renewal requires JMJD1C. J Clin Invest 126:997-1011
Yin, Jie; Leavenworth, Jianmei W; Li, Yang et al. (2015) Ezh2 regulates differentiation and function of natural killer cells through histone methyltransferase activity. Proc Natl Acad Sci U S A 112:15988-93
Perry, Jennifer A; Kiezun, Adam; Tonzi, Peter et al. (2014) Complementary genomic approaches highlight the PI3K/mTOR pathway as a common vulnerability in osteosarcoma. Proc Natl Acad Sci U S A 111:E5564-73
Deshpande, Aniruddha J; Deshpande, Anagha; Sinha, Amit U et al. (2014) AF10 regulates progressive H3K79 methylation and HOX gene expression in diverse AML subtypes. Cancer Cell 26:896-908
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
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
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

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