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Targeting Tumor-Specific Apoptosis Regulation in Advanced ER+ Breast Cancer

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[Technical Report, Annual Report]

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Patients with advanced, ER breast cancer are commonly treated with combinations of anti-estrogen therapies plus CDK46inhibitors. However, once they progress on this therapy, few proven treatment options remain. We recently made the surprising discovery that ER cell lines, xenografts, and patient tumors are highly primed to undergo apoptosis and specifically dependent on the antiapoptotic BCL-2 family proteins BCL-XL and MCL-1 for their survival. Direct, combined BCL-XLMCL-1 inhibition yields synergistic apoptosis induction in cell lines and regressions of tumors in vivo, an effect that can be phenocopied using combinations of BCL-XL and mTOR inhibitors. The goal of this proposal is to build on the above discovery of a breast cancer-specific survival dependency by generating the key data necessary to motivate clinical trials exploring BCL-XL plus mTOR inhibitors in patients who have progressed on anti-estrogen plus CDK46 inhibitor therapy. Specifically, we aim to evaluate the efficacy of combined BCL-XL plus mTOR inhibition in gold standard mouse models, optimize the use of this combination therapy to sensitize tumors to low dose, cytotoxic chemotherapies and fulvestrant, and validate biomarkers that identify the patients most likely to respond to these treatments. Here, we describe key advances occurring during the second year of this award toward the realization of these goals.

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  • Medicine and Medical Research

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[A, Approved For Public Release]