Project Summary/Abstract Prostate cancer incidence in the United States has significantly increased over the last two decades. Despite the improvement of screening strategies, it remains challenging to accurately identify men at greatest risk of progression to aggressive disease, early enough in the course of the disease to implement appropriate measures that would improve their survival chances. In that respect, prostate cancer is governed by profound disparities with African American (AA) men amongst the highest-risk population groups. Several studies suggest a multifactorial etiology for such disparities, encompassing an accumulation of genetic aberrations. However, genome-based prostate cancer biomarker discovery efforts have largely focused on the nuclear genome, overlooking the smaller but essential mitochondrial genome (mtDNA). Indeed, alterations in mtDNA-encoded oxidative phosphorylation (OXPHOS) genes have been associated with increased prostate cancer risk, particularly in AA men, but their exact functional impact remains unknown. Therefore, understanding the underlaying mitochondrial determinants of prostate cancer disparities could ultimately lead to better precision interceptions and biomarkers for stratifying patients that will develop aggressive prostate cancer. The overarching goal of this proposal is to understand how mtDNA alterations, present in aggressive prostate cancer contribute to disease outcomes in high-risk groups and how to use this knowledge for more effective precision cancer interceptions. In particular, my preliminary data strongly suggest an important role for mitochondrial dysfunction in driving aggressive prostate cancer. Given that among other carcinogenic alterations, adaptations in mitochondrial metabolism may contribute to prostate cancer formation and progression, this proposal will leverage unique prostate cancer mouse models of mitochondrial dysfunction to address specific mitochondrial vulnerabilities for cancer precision interceptions. I hypothesize that mitochondrial dysfunction acts a critical driver of aggressive prostate cancer, and that it can be exploited for interceptive purposes. Specifically, in Aim 1, I will identify mtDNA alterations in mtDNA GEMMs and assess their clinical relevance for prostate cancer disparities. In Aim 2, I will use metformin interception as a proof-of-concept for establishing precision strategies targeting mitochondrial dysfunction in prostate cancer. In Aim 3, I will exploit mtDNA GEMMs to investigate how OXPHOS vulnerabilities are linked to mitochondrial metabolic rewiring in aggressive prostate cancer and, identify novel mitochondrial-related biomarkers to improve precision prostate cancer interception. The career development plan outlined in this award leverages my training at Columbia University and an exceptional advisory committee into an innovative research strategy to guide my career into precision approaches for the interception of aggressive prostate cancer. This proposal will provide the conceptual groundwork, preliminary data, and experimental tools for a competitive R01 submission, thus launching my independent career.

Project Narrative Prostate cancer is the second-leading cause of cancer-related deaths in men in the United States, governed by profound disparities in disease aggressiveness, incidence, and mortality. This proposal will perform correlative studies in novel preclinical models and high-risk human prostate cancer to identify previously unrecognized mitochondrial genomic and functional alterations in aggressive prostate cancer. These studies will ultimately result in new precision prostate cancer interceptions that can potentially improve the survival and reduce morbidity in high-risk populations.