Development of Novel Therapeutic Strategies in Human Leukemias

Dana-Farber Cancer Inst, Boston MA

Investigators

Linked publications, trials & patents

Abstract

Overall Program Abstract Our proposal addresses fundamental challenges in the treatment of AML, building on recent advances in drug development and new discoveries in leukemia biology, genetics, and epigenetics. We will systematically study regulators of normal and malignant hematopoiesis, leveraging expertise in BH3 profiling to identify compounds that shift cellular apoptotic threshold (Dr. Anthony Letai), by developing protein degradation as a novel tool to overcome gaps in the druggable proteome (Drs. Benjamin Ebert, Eric Fischer, and Scott Armstrong), and by discovering and developing novel agents to target a variety of dependencies in leukemia, including epigenetic programs (Dr. Armstrong and Dr. Zuzana Tothova). The Program includes productive investigators with an enduring history of collaboration. Through this program, our investigators have led research bringing FLT3 and BCL-2 inhibitors from basic science through to FDA approval for the treatment of AML, have carved out a whole new field drugging the undruggable using targeted protein degradation, and have led DOT1L and Menin inhibitors into clinical trials for patients with for KMT2A- rearranged, NPM1 mutant and NUP98-rearranged leukemias. The proposed projects will exploit major advances in cancer biology, genetics and epigenetics, and drug discovery. To improve on current treatment for leukemia, we will focus on three central themes: (1) Cellular regulation in normal and malignant hematopoiesis. We will study the biology and genetics of hematopoiesis, and evaluate the therapeutic potential in four different areas: mitochondrial sensitivity to the FS-1 BH3 mimetic for BFL-1 inhibition (Project 1), the molecular basis for MYB degradation in response to microtubule destabilization (Project 2), the regulation of KMT2A complex formation and gene expression by Menin (Project 3), and the effects of transcription-coupled DNA-RNA hybrids (R-loops) on chromatin organization and gene regulation (Project 4). (2) Targeting ubiquitin ligase function. Our laboratories have characterized several novel mechanisms of drug-induced degradation of hematopoietic transcription factors with direct therapeutic applications. We will leverage our aggregate expertise in cancer biology, proteomics, genetics and epigenetics, and ubiquitin ligase biology and chemistry to discover and characterize novel protein degraders to target apoptosis, through disruption of BFL-1, MYB degradation via microtubule destabilization, and chromatin maintenance by Menin/KMT2A degradation. (3) Genetic and molecular susceptibilities to therapies. Along with investigating the apoptotic pathways, genetic programs, and chromatin regulatory networks (epigenetics) that contribute to leukemic proliferation, we will focus on the discovery and development of targeted inhibitory and protein degrading compounds and determine their optimal use singly or in combination in AML.