Delineating the mechanisms and clinical utility of mtDNA mutagenesis in cancer

描述癌症 mtDNA 突变的机制和临床应用

• 批准号: 9239202
• 负责人: Jason H Bielas
• 金额: $ 40.26万
• 依托单位: FRED HUTCHINSON CANCER RESEARCH CENTER
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-02-15 至 2022-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9239202
• 关键词: Aerobic; Aging; Apoptosis; Apoptotic; Biological Assay; Cancer Patient; Cell Death; Cells; Cellular Metabolic Process; Cessation of life; Clinic; Clinical; Coupled; DNA; DNA Damage; Data; Development; Eukaryotic Cell; Frequencies; Genes; High Prevalence; Human; Image; Intervention; Life; Literature; Malignant Neoplasms; Measures; Mediating; Metabolism; Mitochondria; Mitochondrial DNA; Modality; Monitor; Mutagenesis; Mutation; Neoadjuvant Therapy; Neoplasm Metastasis; Normal Cell; Normal tissue morphology; Nuclear; Organelles; Oxidative Phosphorylation; Pathologic; Pathway interactions; Patient-Focused Outcomes; Patients; Perfusion; Pharmacology; Positron-Emission Tomography; Production; Prognostic Marker; Quality of life; Reactive Oxygen Species; Relapse; Research; Resistance; Respiration; Role; Testing; Therapeutic; Tissues; Toxic effect; Tumor Biology; Tumor Tissue; Work; base; cancer biomarkers; cancer cell; cancer survival; cancer therapy; carcinogenicity; chemotherapy; experimental study; glucose metabolism; improved; in vivo; innovation; malignant breast neoplasm; mitochondrial DNA mutation; mitochondrial genome; mitochondrial metabolism; neoplastic cell; novel; novel therapeutics; personalized medicine; predictive marker; predictive of treatment response; prognostic; response; targeted treatment; theories; therapy resistant; treatment response; tumor; tumor metabolism; tumor progression

Mitochondria are the intracellular organelles responsible for energy production in eukaryotic cells, and are unique in that they contain their own DNA (mtDNA), which encodes genes important for mitochondrial function. While it has been well-established that nuclear DNA has an increased overall burden of mutations in cancers, we recently discovered that the frequency of random mutations in mtDNA is decreased in human tumors relative to healthy tissues. Furthermore, these novel findings provide the framework for the proposed research. We have since demonstrated that the lower burden of mtDNA mutations in tumor tissue is coupled to a decrease in oxidative phosphorylation (OXPHOS) and, by extension, a reduction in reactive oxygen species (ROS)-mediated mtDNA damage. These novel findings provide the impetus for the proposed research, as they suggest that, unlike in nuclear DNA, an increased rate of mtDNA mutagenesis does not facilitate a cancer’s development; rather, it may hinder it. As such, under the direction of the proposed Specific Aims we expect to delineate the mechanisms underlying mitochondrial mutagenesis in normal and tumor cells, and exploit these for use in the clinic. For the first Aim, we propose to delineate the relationships and among metabolism, ROS, mtDNA mutagenesis, and apoptotic priming by testing the hypothesis that mtDNA mutagenesis mediates apoptotic response. Secondly, we will establish whether mtDNA mutagenesis is predictive of treatment response and thus can serve as a specific, prognostic biomarker of pathological response (pCR) to neoadjuvant treatment in locally advanced breast cancer (LABC). Lastly, we will determine if mitochondrial- targeted cancer therapeutics, focused on directly increasing OXPHOS, will promote apoptotic response and sensitize cancer cells to chemotherapeutically-induced apoptosis. Successful completion of the proposed project Aims will: (1) Establish a cause and effect relationship between glucose metabolism and apoptotic resistance; (2) Advance understanding of relationships between mtDNA mutagenesis, cell metabolism, and cancer; (3) Determine the utility of mitochondrial mutagenesis as a predictive biomarker of treatment response, early relapse, and death; (4) Explore the utility of a novel chemotherapeutic strategy that increases mitochondrial respiration; and (5) ultimately improve cancer prognostication and treatment, thereby improving patient outcomes and quality of life.

线粒体是真核细胞中负责产生能量的细胞内细胞器， 它们的独特之处在于它们含有自己的DNA（mtDNA），它编码对线粒体功能重要的基因。 虽然核 DNA 增加了癌症突变的总体负担，这一点已得到证实， 我们最近发现人类肿瘤中 mtDNA 随机突变的频率降低 此外，这些新发现为拟议的研究提供了框架。 此后我们证明，肿瘤组织中 mtDNA 突变负担较低与 氧化磷酸化 (OXPHOS) 减少，进而减少活性氧 (ROS)介导的线粒体DNA损伤。这些新发现为拟议的研究提供了动力，因为它们 表明，与核 DNA 不同，线粒体 DNA 突变率的增加不会促进癌症的发生 发展；相反，它可能会阻碍它，因此，在我们期望的拟议具体目标的指导下。 描述正常细胞和肿瘤细胞线粒体诱变的机制，并利用这些机制 对于第一个目标，我们建议描述新陈代谢、ROS、 mtDNA 诱变和细胞凋亡引发（通过检验 mtDNA 诱变介导的假设） 其次，我们将确定线粒体DNA突变是否可以预测治疗。 反应，因此可以作为病理反应（pCR）的特异性预后生物标志物 最后，我们将确定局部晚期乳腺癌（LABC）的新辅助治疗。 靶向癌症治疗，重点是直接增加 OXPHOS，将促进细胞凋亡反应和 使癌细胞对化疗诱导的细胞凋亡敏感 成功完成拟议的任务。 项目目标将：（1）建立糖代谢与细胞凋亡之间的因果关系 (2) 加深对mtDNA突变、细胞代谢和线粒体DNA之间关系的理解 癌症；（3）确定线粒体突变作为治疗反应的预测生物标志物的效用， (4) 探索一种新的化疗策略的效用，该策略可增加 线粒体呼吸；（5）最终改善癌症预后和治疗，从而改善 患者的治疗结果和生活质量。