Investigating mitochondrial dysfunction in high-risk prostate cancer

研究高危前列腺癌中的线粒体功能障碍

• 批准号: 10570345
• 负责人: Alexandros Papachristodoulou
• 金额: $ 13.62万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-12 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10570345
• 关键词: Address; Advisory Committees; Affect; African American; Antidiabetic Drugs; Antineoplastic Agents; Automobile Driving; Award; Biological Assay; Biological Markers; Cancer Etiology; Cessation of life; Clinical Research; Complement; Correlative Study; DNA Sequence Alteration; Data; Data Set; Development; Development Plans; Diagnosis; Disease; Disease Outcome; Disparity; Etiology; Functional disorder; Genes; Genetic; Genetic Markers; Genetically Engineered Mouse; Genome; Genomics; Goals; Human; In Vitro; Incidence; Intervention; Investigation; Knowledge; Link; Malignant Neoplasms; Malignant neoplasm of prostate; Measures; Mentors; Metabolic; Metabolic Pathway; Metabolism; Metformin; Mitochondria; Mitochondrial DNA; Modeling; Molecular; Morbidity - disease rate; NKX3-1 gene; Nuclear; Oncogenic; Organoids; Outcome; Oxidative Phosphorylation; Patients; Population Group; Pre-Clinical Model; Prognosis; Prostatic; Publishing; Research; Research Personnel; Risk; Role; Stress; Structure of base of prostate; Training; United States; Universities; Work; anticancer research; biomarker discovery; biomarker driven; cancer biomarkers; cancer health disparity; carcinogenicity; career; career development; clinically relevant; cohort; efficacy evaluation; experience; high risk; high risk men; high risk population; improved; innovation; insight; men; metabolomics; mitochondrial DNA alteration; mitochondrial dysfunction; mitochondrial genome; mitochondrial metabolism; mortality; mouse model; novel; patient stratification; personalized approach; prognostic value; progression risk; prostate cancer progression; prostate cancer risk; racial disparity; racial population; response; screening; skills; specific biomarkers; tool; trait; tumor

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.

项目摘要/摘要 在过去的二十年中，美国的前列腺癌发病率显着增加。 尽管筛查策略有所改善，但准确地确定男性最大的人仍然具有挑战性 在疾病的过程中足够早早地进展到侵略性疾病的风险以实施适当的 可以提高其生存机会的措施。在这方面，前列腺癌受深刻的控制 在最高危险的人口群体中，非裔美国人（AA）男性的差异。一些研究表明 这种差异的多因素病因，包括遗传畸变的积累。然而， 基于基因组的前列腺癌生物标志物发现工作主要集中在核基因组， 俯瞰较小但必不可少的线粒体基因组（mtDNA）。确实，mtDNA编码的改变 氧化磷酸化（OXPHOS）基因与前列腺癌风险增加有关， 特别是在AA男子中，但它们的确切功能影响仍然未知。因此，了解 前列腺癌差异的线粒体决定因素的底层可能最终导致更好的精度 截距和生物标志物，用于整理会发展侵略性前列腺癌的患者。 该提案的总体目标是了解MTDNA的变化如何激进 前列腺癌促进了高风险群体的疾病结局，以及如何使用这些知识以获得更多 有效的精确癌症截距。特别是，我的初步数据强烈地表明了 线粒体功能障碍在驱动攻击性前列腺癌中。考虑到其他致癌改变， 线粒体代谢的适应可能导致前列腺癌的形成和进展，这 建议将利用线粒体功能障碍的独特前列腺癌小鼠模型来解决特定 线粒体脆弱性的癌症精度截距。我假设线粒体功能障碍作用 侵略性前列腺癌的关键驱动因素，可以用于拦截目的。具体来说， 在AIM 1中，我将确定mtDNA GEMM中的mtDNA改变并评估其对前列腺的临床相关性 癌症差异。在AIM 2中，我将使用二甲双胍截距作为概念验证的证明 针对前列腺癌线粒体功能障碍的策略。在AIM 3中，我将利用mtDNA宝石 调查如何将Oxphos脆弱性与侵略性前列腺中的线粒体代谢相关联 癌症并确定新型的线粒体相关生物标志物，以改善前列腺癌的截距。 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 杰出的咨询委员会纳入创新研究策略，以指导我的职业精确 拦截攻击性前列腺癌的方法。该建议将提供概念 竞争性R01提交的基础工作，初步数据和实验工具，从而启动了我 独立职业。