Investigating mitochondrial dysfunction in high-risk prostate cancer

项目摘要/摘要 在过去的二十年里，美国的前列腺癌发病率显著增加。 尽管筛查策略有所改进，但要准确识别最多的男性仍然具有挑战性 有发展为侵袭性疾病的风险，在疾病病程足够早的情况下适当实施 这些措施将提高它们的生存机会。在这方面，前列腺癌是由深刻的 在高危人群中与非裔美国人(AA)男性的差距。几项研究表明 这种差异的多因素病因学，包括遗传异常的积累。然而， 基于基因组的前列腺癌生物标记物发现工作主要集中在核基因组上， 忽视了较小但必不可少的线粒体基因组(MtDNA)。事实上，线粒体DNA编码的变化 氧化磷酸化(OXPHOS)基因与前列腺癌风险增加有关， 尤其是在AA男性中，但它们对功能的确切影响尚不清楚。因此，理解 前列腺癌差异的线粒体决定因素可能最终导致更高的精确度 截取和生物标志物用于对将发展为侵袭性前列腺癌的患者进行分层。 这项提案的首要目标是了解线粒体DNA改变是如何以侵略性的方式出现的 前列腺癌对高危人群的疾病结局有贡献，以及如何利用这一知识获得更多 有效的癌症精准拦截。特别是，我的初步数据强烈表明， 线粒体功能障碍与侵袭性前列腺癌的关系。考虑到在其他致癌变化中， 线粒体代谢的适应性可能有助于前列腺癌的形成和发展，这 提案将利用独特的前列腺癌小鼠线粒体功能障碍模型来解决特定的 线粒体对癌症精确截获的脆弱性。我假设线粒体功能障碍 它是侵袭性前列腺癌的关键驱动力，它可以被用于拦截目的。具体来说， 在目标1中，我将识别mtDNA GEMM中的mtDNA变化，并评估它们与前列腺癌的临床相关性 癌症差异。在目标2中，我将使用二甲双胍拦截作为确定精确度的概念验证 针对前列腺癌线粒体功能障碍的策略。在目标3中，我将利用mtDNA GEMM来 研究侵袭性前列腺癌患者OXPHOS缺陷与线粒体代谢重排的关系 癌症和，确定新的线粒体相关生物标记物，以提高前列腺癌的精确度拦截。 该奖项中概述的职业发展计划利用了我在哥伦比亚大学的培训和 将卓越的咨询委员会转化为创新的研究战略，以指导我的职业生涯走向精准 拦截侵袭性前列腺癌的方法。这项提案将提供概念性的 为竞争性R01提交的基础工作、初步数据和实验工具，从而启动我的 独立的事业。

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.