The overall goal of the parent award is to identify targeted agents that are either effective on their own in triple negative breast cancer (TNBC), or that can overcome resistance to commonly used first line chemotherapeutics that are currently given as part of clinical standard of care regimens. Our multi-omic profiling of 50 TNBC PDX models annotated with chemotherapy response data identified mitochondrial metabolism as one of the top networks associated with chemoresistance to both docetaxel and carboplatin, alone and in combination. Perhaps most importantly, of the 42 PDX treated with single agent docetaxel or carboplatin and the combination, 10 (24%) failed to show a partial or complete response to any of the three treatments, and thus are essentially completely resistant to these agents. Our molecular analyses of baseline PDX omics has identified oxidative phosphorylation (oxphos) and mitochondrial transcription and translation as major processes associated with resistance to both docetaxel and carboplatin as single agents, as well as the combination. We obtained similar results in past studies using AC treatment1. Similar results were also observed in an analysis of a recent unpublished clinical trial (CADENCE, NCT02547987). In an attempt to overcome this resistance, we will test the efficacy of two novel small molecule inhibitors of mitochondrial functions, either singly or in combination with standard of care taxane or platinum chemotherapy agents. We will evaluate these treatments in six extensively characterized PDX models of TNBC that we have identified to be most resistant to single and combination chemotherapy treatment, and that express higher levels of the two drug targets. LDC204857 (Lead Discovery Center of Germany) is an inhibitor of mitochondrial RNA polymerase, thus inhibiting mitochondrial transcription. This in turn disrupts production of the electron transport chain (ETC) and oxidative phosphorylation (oxphos). ONC206 (Chimerix Inc) is an agonist of the mitochondrial protease ClpP and inhibitor of dopamine receptor D2, thus inhibiting ETC super-complex assembly and oxphos. We have accrued promising results with these agents in human TNBC cell lines and both are ready for clinical translation.