Description:

The Department of Biochemistry and Molecular Genetics presents:

Kapil Bhalla, MD
Professor, Department of Leukemia, Division of Cancer Medicine and Kelcie Kana Research Chair
University of Texas MD Anderson Cancer Center

Presentation:

"Pre-clinical efficacy of targeted inhibition of Chromatin remodeler ATPases in models of high-risk AML"

Abstract: BRG1 (SMARCA4) and BRM (SMARCA2) are the core ATPase within the multi-protein, ATP-dependent, chromatin remodeling BAF complexes that regulate gene transcription. FHD-286 is a potent, selective, orally administered, inhibitor of BRG1/BRM in early clinical development as a therapy for AML. This presentation will describe the pre-clinical in vitro and in vivo efficacy FHD-286 in models of high-risk AML. Treatment with FHD-286 for 4 to 7 days induced morphologic features of differentiation and loss of viability in AML cell lines and patient-derived (PD) AML cells with MLLr or mtNPM1. Notably, FHD-286 also induced significant lethality in Menin inhibitor (MI) resistant AML cell lines and PD AML cells lacking Menin mutations. ChIP-Seq, ATAC-Seq, RNA-Seq, Mass spectrometry and CyTOF analyses data will be presented to define gene-expressions alterations that correlate with the lethal effects of FHD-286. Findings from a domain-specific CRISPR screen targeting epigenetic regulators revealed significant co-enrichments with FHD-286 treatment of the gRNAs against BRD4 and LSD1, suggesting them as the epigenetic mediators of FHD-286 resistance. Co-treatment with FHD-286 and venetoclax, BET inhibitor, decitabine or MI (SNDX-50469) exerted synergistic lethality in AML cell lines and PD AML cells with MLL1r or mtNPM1. In a PD xenograft (PDX) model of MLL1r AML with FLT3 mutation, monotherapy with FHD-286 for 4 to 6-weeks was significantly effective in reducing AML burden and improving overall survival. Separately, in vivo FHD-286 treatment vs vehicle control, also significantly inhibited the AML-initiating potential of AML stem progenitor cells. Additionally, co-treatment with FHD-286 and decitabine or BET inhibitor vs each drug alone, or vehicle control, significantly reduced the AML burden and improved survival, without significant toxicity in the PDX models of MLLr or mtNPM1, as well as of MECOM rearranged AML. Finally, co-treatment with FHD-286 and MI was significantly more effective than each drug alone in reducing the AML burden and overall survival of mice engrafted with a separate PDX model of AML cells with mtNPM1 and FLT3-ITD, without significant toxicity. These findings demonstrate the pre-clinical efficacy of FHD-286-based rational combinations and support their clinical testing in the high-risk AML models.

Host: Dr. Lu Wang, Assistant Professor, Biochemistry and Molecular Genetics