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.

 描述（由申请人提供）： 肾细胞癌（RCC）是男性和女性中最常见的10种恶性肿瘤之一。自2009年以来，超过30，000名退伍军人被诊断患有这种恶性肿瘤。不幸的是，晚期疾病患者的治疗进展一直在增加，新的治疗方法是必要的。代谢改变，恶性肿瘤的一个既定标志，可能提供新的治疗机会。然而，肾肿瘤重塑代谢的分子机制仍然知之甚少。新出现的证据表明，协调重塑线粒体代谢途径在肾癌，包括三羧酸（TCA）循环和氧化磷酸化。这种重塑可能导致向糖酵解的转变（即瓦尔堡表型）。长期目标是确定肾癌重塑代谢的分子基础，并利用这些知识合理开发新的治疗方法，改善患者的预后。这个建议的目的是确定RCC重塑线粒体代谢的转录基础，并确定对肿瘤发生的影响。我们的中心假设是转录因子PRDM 16（PRD 1-BF 1-RIZ 1同源结构域包含16）的表观遗传沉默促进RCC中驱动肿瘤发生的代谢开关。该假设基于申请人实验室的患者来源的样品（正常肾脏、原发性肿瘤和转移性肿瘤沉积物）的初步数据，其证明PRDM 16损失是该恶性肿瘤中最显著改变的基因表达变化之一。提出研究的理由是，了解肿瘤代谢重塑发生的分子基础将揭示可用于治疗的代偿途径和脆弱性。我们的中心假设，基于强有力的初步数据，将通过追求以下具体目标来检验：1）确定PRDM 16调节TCA循环酶表达的转录基础; 2）确定PRDM 16缺失促进肿瘤代谢转变的机制;以及3）确定PRDM 16在RCC中丢失的表观遗传基础以及这种丢失对肿瘤发生的贡献。这项研究意义重大，因为它将在可靶向途径的背景下确定RCC代谢转变的新驱动因素。这种方法是创新的，因为它将建立表观基因组和肿瘤代谢之间的联系。最终，所收集的知识有可能提高晚期RCC退伍军人的治疗效果，这是一个未满足的需求，挑战了这种疾病的当代管理。