Role of targeting ATPases BRG1/BRM in therapy of AML

University Of Tx Md Anderson Can Ctr, Houston TX

Investigators

Abstract

Project Summary: BAF (BRG1/BRM-associated factor) complexes are ATP dependent chromatin-remodeling complexes which contain mutually exclusive, core ATPases, BRG1 (SMARCA4) and BRM (SMARCA2). The canonical (c) BAF complex subunits bind and allow transcription factors (TFs) and co-factors to gain access to the chromatin and modulate lineage-specific gene transcription in hematopoiesis. BRG1 is a dependency in AML cells, including those with MLL rearrangement (MLLr) or mutant (mt) NPM1, representing 40% of adult AML. Although Menin inhibitors (MIs) induce clinical remissions, most patients of AML with MLLr or mtNPM1 relapse with MI-resistant AML, based on adaptive, dysregulated gene-expressions or hotspot mutations in Menin, abrogating MI activity in AML cells. This creates a glaring unmet need to develop and test through preclinical studies novel targeted agents and combinations with superior efficacy that can be advanced to the clinical setting in AML with MLLr or mtNPM1. FHD-286 is the first in clinic (NCT04891757), potent, catalytic inhibitor, whereas AU15330 is the PROTAC (Proteolysis Targeted Chimera) degrader of BRG1/BRM. Our preliminary studies demonstrate that treatment with FHD-286 induces differentiation and lethality in AML cells, regardless of sensitivity to MI, but not in normal progenitor cells. This compelling efficacy is associated with gene-expression perturbations responsible for growth inhibition, differentiation, and depleted AML-initiating potential in patient-derived (PD) xenograft (PDX) models of AML with MLLr or mtNPM1. FHD-286 monotherapy, and in combinations with standard and investigational agents, also exerts potent efficacy in cellular models of AML harboring MLLr and mtNPM1 with or without FLT3 mutations. Studies proposed here are supported by these compelling preliminary findings and our access to the pre-treatment and upon-relapse AML cells from patients enrolled on MI monotherapy. These studies are motivated by the overarching hypothesis that treatment with BRG1/BRM antagonist will undermine dysregulated gene expressions and overcome differentiation-arrest, growth advantage and survival of AML cells, as well as synergistically exert in vivo efficacy against PDX models of AML with MLLr or mtNPM1. The specific aims of studies proposed are: Aim 1: To determine pre-clinical efficacy of BRG1/BRM antagonist (an inhibitor or degrader) and associated perturbations in the epigenome and transcriptome, linked to the proteome, evaluated as the gene-expression perturbation signature of BRG1/BRM antagonist activity in PD AML cells with MLLr or mtNPM1 sensitive or resistant to MI treatment. Aim 2: To evaluate the pre-clinical efficacy of BRG1/BRM antagonist-based novel combinations, utilizing in vitro MI-sensitive PD AML cells and in vivo PDX models of AML with MLL1r or mtNPM1. Aim 3: To determine efficacy of BRG1/BRM antagonist-based combinations to overcome MI-resistance due to epigenetic/adaptive mechanisms or Menin mutations in PD AML cells with MLL1r or mtNPM1.