权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

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

基本信息

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
项目类别：
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

项目摘要

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.

项目总结/摘要在过去的二十年中，美国前列腺癌的发病率显著增加。尽管筛查策略有所改进，但在最大程度上准确识别男性仍然具有挑战性。进展为侵袭性疾病的风险，在疾病过程中尽早实施适当的这些措施将提高他们的生存机会。在这方面，前列腺癌是由深刻的与非洲裔美国人（AA）男性在最高风险人群中的差异。几项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，在这方面，基于基因组的前列腺癌生物标志物发现努力主要集中在核基因组上，忽略了较小但重要的线粒体基因组（mtDNA）。事实上，线粒体DNA编码的氧化磷酸化（OXPHOS）基因与前列腺癌风险增加有关，特别是在AA男性中，但其确切的功能影响仍然未知。因此了解前列腺癌差异的线粒体决定因素可能最终导致更好的精确度拦截和生物标志物，用于对将发展为侵袭性前列腺癌的患者进行分层。这项提议的首要目标是了解线粒体DNA的改变，如何在侵袭性前列腺癌有助于高危人群的疾病结局，以及如何利用这些知识进行更多的研究。有效的精确癌症拦截。特别是，我的初步数据强烈表明，线粒体功能障碍导致侵袭性前列腺癌。鉴于在其他致癌改变中，线粒体代谢的适应可能有助于前列腺癌的形成和发展，该提案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的线粒体的弱点来精确拦截癌症。我假设线粒体功能障碍它是侵袭性前列腺癌的关键驱动因素，并且可以用于拦截目的。具体地说，在目的1中，我将鉴定mtDNA GEMM中mtDNA的改变，并评估它们与前列腺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建立精密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OXPHOS漏洞如何与侵袭性前列腺中的线粒体代谢重新布线有关癌症，并确定新的前列腺相关生物标志物，以提高精确的前列腺癌拦截。这个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，卓越的咨询委员会转变为创新的研究战略，以指导我的职业生涯走向精准前列腺癌的治疗方法该提案将提供概念上的基础，初步数据和实验工具的竞争R 01提交，从而启动我的独立的职业生涯。