The overall goal of this program is to develop more effective and less toxic therapies for the treatment of leukemia. Tremendous progress has been made in recent years in understanding the genetic and molecular basis of acute myeloid leukemia (AML), but progress towards improving outcomes for patients have been more limited. We will evaluate the efficacy and mechanistic basis for a set of novel therapeutic strategies for the treatment of AML. Specifically, we will investigate the modulation of apoptotic threshold in Project 1; inhibition of a specific ubiquitin ligase, CRL4-CRBN, by lenalidomide to induce cell cycle arrest, apoptosis, and differentiation; targeting lysine acetyltransferase activity to alter he function of transcription factors that are critical for AML biology in Project 3; and targeting key epigenetic regulators, BET bromodomain proteins and DOT1L, in Project 4. In addition to hypothesis-driven investigation of the biological mechanisms relevant to each therapeutic approach, we will investigate the therapeutic potential of these approaches using common assays and models. These therapeutic approaches will be investigated both individually and in combinations with existing therapies and each other. We will test molecules in vitro using dynamic BHS profiling, developed by Dr. Letai (Project 1) to examine the impact of candidate small molecules on apoptotic threshold. We will test molecules in vivo using both murine models developed by Dr. Bradner (Project 4) and primary human AML samples in xenograft models (Dr. Griffin, Core B). The most promising treatments will be brought forward to clinical trials in Core D. We will prospectively identify the subgroups most likely to respond by deep genetic and molecular characterization of AML samples used for pre-clinical and clinical studies. In aggregate, these studies will lead to the advancement of novel therapies for the treatment of AML, identification of genetic subgroups that are most likely to respond to novel treatments, and insights into the biological mechanisms of action for novel therapeutic strategies.
The overall goal of this program is to develop more effective and less toxic therapies for the treatment of leukemia. We will explore the targeting of epigenetic regulators, ubiquitin ligases, lysine acetyltransferases, and modulators of apoptotic threshold. Following pre-clinical studies in common model systems, the most promising therapies will be tested in clinical trials with deep molecular characterization of patient samples.
|Sridhar, Radhakrishnan; Takei, Hisashi; Syed, Riyaz et al. (2018) Styryl Quinazolinones as Potential Inducers of Myeloid Differentiation via Upregulation of C/EBP?. Molecules 23:|
|Chu, S Haihua; Song, Evelyn J; Chabon, Jonathan R et al. (2018) Inhibition of MEK and ATR is effective in a B-cell acute lymphoblastic leukemia model driven by Mll-Af4 and activated Ras. Blood Adv 2:2478-2490|
|Wang, Jinhua; Erazo, Tatiana; Ferguson, Fleur M et al. (2018) Structural and Atropisomeric Factors Governing the Selectivity of Pyrimido-benzodiazipinones as Inhibitors of Kinases and Bromodomains. ACS Chem Biol 13:2438-2448|
|Sievers, Quinlan L; Gasser, Jessica A; Cowley, Glenn S et al. (2018) Genome-wide screen identifies cullin-RING ligase machinery required for lenalidomide-dependent CRL4CRBN activity. Blood 132:1293-1303|
|Cortes, Jorge E; Douglas Smith, B; Wang, Eunice S et al. (2018) Glasdegib in combination with cytarabine and daunorubicin in patients with AML or high-risk MDS: Phase 2 study results. Am J Hematol 93:1301-1310|
|Fathi, Amir T; Erba, Harry P; Lancet, Jeffrey E et al. (2018) A phase 1 trial of vadastuximab talirine combined with hypomethylating agents in patients with CD33-positive AML. Blood 132:1125-1133|
|Cortes, Jorge; Tamura, Kenji; DeAngelo, Daniel J et al. (2018) Phase I studies of AZD1208, a proviral integration Moloney virus kinase inhibitor in solid and haematological cancers. Br J Cancer 118:1425-1433|
|Cusan, Monica; Cai, Sheng F; Mohammad, Helai P et al. (2018) LSD1 inhibition exerts its antileukemic effect by recommissioning PU.1- and C/EBP?-dependent enhancers in AML. Blood 131:1730-1742|
|Postalcioglu, Merve; Kim, Haesook T; Obut, Faruk et al. (2018) Impact of Thrombotic Microangiopathy on Renal Outcomes and Survival after Hematopoietic Stem Cell Transplantation. Biol Blood Marrow Transplant 24:2344-2353|
|DiNardo, Courtney D; Pratz, Keith; Pullarkat, Vinod et al. (2018) Venetoclax combined with decitabine or azacitidine in treatment-naive, elderly patients with acute myeloid leukemia. Blood :|
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