3 OVERALL PROGRAM CRITIQUE 3 PROGRESS DURING THE CURRENT FUNDING PERIOD 3 PROGRAM LEADERSHIP 3 PROGRAM AS AN INTEGRATED EFFORT 3 COLLABORATING INSTITUTIONS 4 PROJECT AND CORE SUMMARIES OF DISCUSSION 4 PROTECTION OF HUMAN SUBJECTS 5 VERTEBRATE ANIMALS 5 ADDITIONAL REVIEW CONSIDERATIONS 6 PROJECT 1: Mitochondrial Determination of Response to Targeted AML Therapies 7 PROJECT 2: Determination of the Mechanism of Lenalidomide Activity in Acute Myeloid Leukemia 8 PROJECT 3: Lysine Acetyltransferases in Myelopoiesis and Leukemia 10 PROJECT 4: Novel Epigenetic Approaches in AML 11 CORE A: Administrative Core 13 CORE B: Sample Processing and Analysis Core 14 CORE C: Biostatistics 16 CORE D: Clinical Research Support Core 16 COMMITTEE BUDGET RECOMMENDATIONS 19 SPECIAL EMPHASIS PANEL ROSTER DESCRIPTION (provided by applicant): 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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
2P01CA066996-16A1
Application #
8666227
Study Section
Special Emphasis Panel (ZCA1-RPRB-C (J1))
Program Officer
Merritt, William D
Project Start
1997-04-25
Project End
2019-08-31
Budget Start
2014-09-16
Budget End
2015-08-31
Support Year
16
Fiscal Year
2014
Total Cost
$2,307,647
Indirect Cost
$229,184
Name
Brigham and Women's Hospital
Department
Type
DUNS #
030811269
City
Boston
State
MA
Country
United States
Zip Code
02115
Hemming, Matthew L; Lawlor, Matthew A; Zeid, Rhamy et al. (2018) Gastrointestinal stromal tumor enhancers support a transcription factor network predictive of clinical outcome. Proc Natl Acad Sci U S A 115:E5746-E5755
Kardosova, Miroslava; Zjablovskaja, Polina; Danek, Petr et al. (2018) C/EBP? is dispensable for steady-state and emergency granulopoiesis. Haematologica 103:e331-e335
Numata, Akihiko; Kwok, Hui Si; Kawasaki, Akira et al. (2018) The basic helix-loop-helix transcription factor SHARP1 is an oncogenic driver in MLL-AF6 acute myelogenous leukemia. Nat Commun 9:1622
Brown, Fiona C; Still, Eric; Koche, Richard P et al. (2018) MEF2C Phosphorylation Is Required for Chemotherapy Resistance in Acute Myeloid Leukemia. Cancer Discov 8:478-497
Manley, Paul W; Weisberg, Ellen; Sattler, Martin et al. (2018) Midostaurin, a Natural Product-Derived Kinase Inhibitor Recently Approved for the Treatment of Hematological MalignanciesPublished as part of the Biochemistry series ""Biochemistry to Bedside"". Biochemistry 57:477-478
Ebert, Benjamin L; Libby, Peter (2018) Clonal Hematopoiesis Confers Predisposition to Both Cardiovascular Disease and Cancer: A Newly Recognized Link Between Two Major Killers. Ann Intern Med 169:116-117
DiNardo, Courtney D; Pratz, Keith W; Letai, Anthony et al. (2018) Safety and preliminary efficacy of venetoclax with decitabine or azacitidine in elderly patients with previously untreated acute myeloid leukaemia: a non-randomised, open-label, phase 1b study. Lancet Oncol 19:216-228
Brien, Gerard L; Remillard, David; Shi, Junwei et al. (2018) Targeted degradation of BRD9 reverses oncogenic gene expression in synovial sarcoma. Elife 7:
Weinberg, Olga K; Gibson, Christopher J; Blonquist, Traci M et al. (2018) Association of mutations with morphological dysplasia in de novo acute myeloid leukemia without 2016 WHO Classification-defined cytogenetic abnormalities. Haematologica 103:626-633
Hoshii, Takayuki; Cifani, Paolo; Feng, Zhaohui et al. (2018) A Non-catalytic Function of SETD1A Regulates Cyclin K and the DNA Damage Response. Cell 172:1007-1021.e17

Showing the most recent 10 out of 376 publications