Targeting Metabolic Vulnerabilities of Triple Negative Breast Cancer Stem Cells

PROJECT SUMMARY/ABSTRACT Triple negative breast cancer (TNBC) is the most aggressive subtype with increased propensity for metastasis and few treatment options. Mounting evidence suggests that cancer stem-like cells (CSCs) in TNBC contribute to the early recurrence and poor clinical outcomes. Thus, identification of novel therapeutic approaches effectively targeting CSCs is crucial for improving outcome in TNBC. We propose to target CSCs in TNBC by exploiting their overexpression of two redox regulating enzymes, NQO1 and SOD1 as a therapeutic vulnerability. Utilizing a potent NQO1-bioactivatable redox cycling compound, IB-DNQ, which generates large amounts of reactive oxygen species in CSCs via futile redox cycling, we propose to examine the feasibility of utilizing IB- DNQ alone, or in combination with SOD1 inhibition, to effectively target CSCs across the EMT-MET CSC state continuum. We will address three specific aims: 1) To demonstrate the efficacy of IB-DNQ alone or in combination with SOD1 inhibition in targeting CSCs in vitro and in mouse models of human TNBC; 2) To determine the mechanisms of cell death induced by IB-DNQ based pro-oxidant strategies; and 3) To determine how IB-DNQ based pro-oxidant strategies modulate antitumor immunity in immunocompetent mouse models. This proposal will evaluate a novel pro-oxidant-based approach in selectively targeting CSCs in TNBC and elucidate the mechanism of action for futile oxidant generators in activating mitochondrial apoptotic and pyroptotic cell death with resultant stimulation of antitumor immunity. As NQO1 and SOD1 are overexpressed in many solid tumors, this therapeutic strategy may have wide applicability.