Resistance to chemotherapy, strongly associated with relapse in triple negative breast cancer (TNBC) remains a major clinical problem. Our goal is to preclinically develop a novel therapeutic strategy to improve chemotherapy efficacy in TNBC to ultimately inform a first-in-human clinical trial. Ultimately, our findings could help deescalate doses of toxic chemotherapies, resulting in quality-of-life improvements for TNBC patients.       

Our team’s published and preliminary data, generated in human TNBC cells cultured in petri dishes, patient derived xenograft mouse models (PDX), immune-competent mouse models, and human TNBC biopsies obtained from the clinic, provide strong evidence for the important role of mitochondria in TNBC chemoresistance. Mitochondria, commonly deemed the ‘powerhouse’ of the cell, are multi-faceted ‘machines’ within cells that generate most of the the cell’s energy and are responsible for numerous cellular processes. Importantly, we have shown that inhibition of mitochondrial processes can enhance sensitivity to chemotherapies commonly used in the TNBC clinic.

For this reason, we tested a novel mitochondria inhibitor, IMT (inhibitor of mitochondrial transcription), in TNBC. This blocks the mitochondria from producing its components required for proper mitochondrial functioning. IMT is exceptionally well tolerated in mice and shows great efficacy in our models for blocking mitochondrial function. We have generated preliminary data to support our hypothesis that IMT disrupts mitochondrial function in TNBC to improve chemotherapeutic response. The studies proposed in our U-Pilot application will help us develop a feasible, quantitative biomarker of IMT response in our preclinical models that we anticipate will help inform future clinical strategies. Our collaborative team is well poised to carry out these studies successfully. We are confident that completion of this proposal will help inform a first in human clinical trial for TNBC, which we are in early stages of designing with our collaborators.