Reprogramming of Mitochondrial Metabolism in Renal Cancer

肾癌线粒体代谢的重编程

• 批准号: 9076121
• 负责人: SUNIL SUDARSHAN
• 金额: --
• 依托单位: BIRMINGHAM VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-04-01 至 2019-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9076121
• 关键词: Affect; Automobile Driving; Biogenesis; Citric Acid Cycle; Clinic; Clinical; DNA Methylation; DNA Modification Process; Data; Deposition; Development; Diagnosis; Disease; Disease Management; Disease Progression; Enzymes; Epigenetic Process; FOXG1B gene; Face; Fumarate Hydratase; Gene Expression; Genetic Transcription; Glycolysis; Goals; Health; Histones; In Vitro; Individual; Kidney; Kidney Neoplasms; Knowledge; Laboratories; Lead; Link; Malignant Epithelial Cell; Malignant Neoplasms; Mediating; Messenger RNA; Metabolic; Metabolic Pathway; Metabolism; Metastatic Renal Cell Cancer; Methylation; Mitochondria; Molecular; Neoplasm Metastasis; Outcome; Oxidative Phosphorylation; PPAR gamma; Pathway interactions; Patient-Focused Outcomes; Patients; Phenotype; Primary Neoplasm; Proteins; Renal Cell Carcinoma; Renal carcinoma; Reporting; Research; Resistance; Respiratory Chain; Role; Sampling; Testing; The Cancer Genome Atlas; Treatment Efficacy; Veterans; Woman; Work; advanced disease; base; clinically relevant; epigenome; estrogen-related receptor; histone modification; improved; improved outcome; in vivo; information gathering; innovation; insight; mRNA Expression; men; metabolic profile; mitochondrial metabolism; novel; novel strategies; novel therapeutic intervention; novel therapeutics; outcome forecast; targeted treatment; transcription factor; treatment strategy; tumor; tumor growth; tumor metabolism; tumorigenesis; tumorigenic

 DESCRIPTION (provided by applicant): Renal cell carcinoma (RCC) is among the 10 most common malignancies in both men and women. Since 2009, over 30,000 Veterans have been diagnosed with this malignancy. Unfortunately, progress in the treatment of patients with advanced disease has been incremental, and new treatment approaches are warranted. Altered metabolism, an established hallmark of malignancy, may provide novel therapeutic opportunities. However, the molecular mechanisms by which kidney tumors remodel metabolism remain poorly understood. Emerging evidence demonstrates coordinated remodeling of mitochondrial metabolic pathways in renal cancer, including the tricarboxylic acid (TCA) cycle and oxidative phosphorylation. This remodeling could lead to a shift toward glycolysis (i.e. the Warburg phenotype). The long-term goal is to identify the molecular basis by which kidney cancer remodels metabolism and to use this knowledge to rationally develop new therapeutic approaches that improve patient outcomes. The objective of this proposal is to define the transcriptional basis by which RCC remodels mitochondrial metabolism and to determine the effects on tumorigenesis. Our central hypothesis is that epigenetic silencing of the transcription factor PRDM16 (PRD1-BF1-RIZ1 homologous domain containing 16) promotes a metabolic switch in RCC that drives tumorigenesis. This hypothesis is based on preliminary data of patient-derived samples (normal kidney, primary tumor, and metastatic tumor deposits) by the applicant's laboratory that demonstrates PRDM16 loss among the most significantly altered gene expression changes in this malignancy. The rationale for the proposed studies is that understanding the molecular basis by which tumor metabolic remodeling occurs will uncover compensatory pathways and vulnerabilities that can be therapeutically exploited. Our central hypothesis, based on strong preliminary data, will be tested through pursuit of the following specific aims: 1) Determine the transcriptional basis by which PRDM16 regulates the expression of TCA cycle enzymes; 2) Determine the mechanisms by which PRDM16 loss promotes a shift in tumor metabolism; and 3) Determine the epigenetic basis by which PRDM16 is lost in RCC and the contribution of this loss to tumorigenesis. The proposed research is significant because it will identify novel drivers of the metabolic shift in RCC in the context of targetable pathways. The approach is innovative because it will establish a link between the epigenome and tumor metabolism. Ultimately, the knowledge gathered has the potential to improve the efficacy of treatment for Veterans with advanced RCC, an unmet need challenging the contemporary management of this disease.