The recent demonstration that the histone methyltransferase, D0T1L and the acetylysine binding protein BRD4 are required for continued proliferation and survival for subsets of acute myelogenous leukemia (AML) cells points to epigenetic mechanisms as potential therapeutic targets in this disease. Small molecule inhibitors of D0T1L and BRD4 have been developed and show remarkable antiproliferative activity against AML cells providing further rationale for deeper characterization of these processes. The central hypothesis for this project is that small molecule inhibitors of epigenetic mechanisms will effectively target AML cells. We will assess this hypothesis through the use novel small molecules, chemical biological approaches, epigenomic analyses genetically engineered mouse models and genetic screens.
In specific Aim 1 we will define the mechanisms by which bromodomains inhibitors suppress Myc and E2F driven gene expression programs.
In specific Aim 1 1 we will define mechanisms of acquired resistance to small molecule bromodomain inhibitors. These studies will inform as to possible mechanisms of clinical resistance to such therapies, and illuminate the cellular pathways through which these molecules suppress proliferation and induce apoptosis.
In specific aim 3 we will assess compelling combinations of small molecule inhibitors of epigenetic pathways including the combination of DOTI L inhibitors and BET inhibitors. Given our access to newly developed small molecule inhibitors, the proposed studies have the potential to bring new, more efficacious, less toxic therapies to children and adults diagnosed with AML.
Recent discoveries suggest that targeting epigeneitc mechansims will be a new approach to cancer therapy. We have recently discovered two proteins that influence gene expression via epigenetic mechasnisms which are required for survival of acute myelogenous leuekmia cells. In this proposal we will define the mechanism of action of these proteins, define mechansims of resitance to inhibtiors of these epigenetic mechanisms, and begin to translate these approaches to clinical assessment.
|Townsend, Elizabeth C; Murakami, Mark A; Christodoulou, Alexandra et al. (2016) The Public Repository of Xenografts Enables Discovery and Randomized Phase II-like Trials in Mice. Cancer Cell 29:574-86|
|Arreba-Tutusaus, P; Mack, T S; Bullinger, L et al. (2016) Impact of FLT3-ITD location on sensitivity to TKI-therapy in vitro and in vivo. Leukemia 30:1220-5|
|Tanaka, Minoru; Roberts, Justin M; Seo, Hyuk-Soo et al. (2016) Design and characterization of bivalent BET inhibitors. Nat Chem Biol 12:1089-1096|
|Wu, H; Hu, C; Wang, A et al. (2016) Discovery of a BTK/MNK dual inhibitor for lymphoma and leukemia. Leukemia 30:173-81|
|Wu, H; Hu, C; Wang, A et al. (2016) Ibrutinib selectively targets FLT3-ITD in mutant FLT3-positive AML. Leukemia 30:754-7|
|Puram, Rishi V; Kowalczyk, Monika S; de Boer, Carl G et al. (2016) Core Circadian Clock Genes Regulate Leukemia Stem Cells in AML. Cell 165:303-16|
|Brien, Gerard L; Valerio, Daria G; Armstrong, Scott A (2016) Exploiting the Epigenome to Control Cancer-Promoting Gene-Expression Programs. Cancer Cell 29:464-76|
|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|
|Schneider, Rebekka K; Schenone, Monica; Ferreira, Monica Ventura et al. (2016) Rps14 haploinsufficiency causes a block in erythroid differentiation mediated by S100A8 and S100A9. Nat Med 22:288-97|
|Hatcher, John M; Weisberg, Ellen; Sim, Taebo et al. (2016) Discovery of a Highly Potent and Selective Indenoindolone Type 1 Pan-FLT3 Inhibitor. ACS Med Chem Lett 7:476-81|
Showing the most recent 10 out of 280 publications