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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/文摘