Targeting BFL-1 in Acute Myelogenous Leukemia

Dana-Farber Cancer Inst, Boston MA

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Abstract

PROJECT SUMMARY Targeting BCL-2 represents a major advance in the treatment of acute myelogenous leukemia (AML). However, roughly 35% of treatment-naïve patients and 70% of patients who relapse after standard chemotherapy induction do not respond to the BCL-2 antagonist venetoclax. There are other anti-apoptotic proteins BCL-2 family proteins that are potential targets in AML. There have been recent attempts to target MCL-1, but cardiac toxicity has been observed in some patients treated with MCL-1 antagonists. While it may be possible to overcome this liability, it is prudent to investigate alternative proteins. BFL-1 (also known as A1) is another anti-apoptotic protein that is expressed in myeloblasts. Like BCL-2 and MCL-1, it inhibits apoptosis by binding pro-apoptotic proteins using a hydrophobic BH3-binding groove that is similar to but functionally distinct from the others. We have previously used BH3 profiling to identify BCL-2 dependence in AML and guide pre-clinical and clinical development of venetoclax in AML. With collaborators, we have previously identified a BH3 peptide, FS-1, that binds BFL-1, but no other anti-apoptotic protein, with high affinity. When used in our BH3 profiling assay, therefore, mitochondrial sensitivity to FS-1 identifies cells that are BFL-1 dependent, and hence candidates for a putative small molecule inhibitor of BFL-1. We have identified BFL-1 dependence in a subset of AML patients. While there are some reports of attempts to identify drugs that target BFL-1, none have yet made it into the clinic, or even advanced pre-clinical studies. Here we propose a Project to better understand BFL-1 dependence in AML, to test the efficacy of BFL-1 inhibition in AML, and to develop small molecules selectively targeting BFL-1. Our laboratory has a unique array of tools we can deploy for this study, including recombinant BFL-1 protein, BH3 profiling, cellular and mitochondrial models of BFL-1 dependence, a peptide tool BFL-1 inhibitor compound, and AML patient-derived xenograft (PDX) models. In addition to our biological studies, we propose medicinal chemistry experiments to improve existing BFL-1 targeting efforts. Other putative BFL-1 inhibitors we will test include existing BH3 mimetic lead compounds, CDK9 inhibitors, FOXM1 inhibitors, and others discovered from our functional screens. The output of this Project will be a comprehensive understanding of the utility of targeting BFL-1 in AML, biomarkers associated with response to BFL-1 inhibitors and improved single agent and combination therapies that target BFL-1 in AML.