Reprogramming of Mitochondrial Metabolism in Renal Cancer

 描述(由申请人提供)： 肾细胞癌(RCC)是男性和女性最常见的10种恶性肿瘤之一。自2009年以来，已有超过3万名退伍军人被诊断出患有这种恶性肿瘤。不幸的是，晚期疾病患者的治疗进展是渐进的，需要新的治疗方法。新陈代谢改变是恶性肿瘤的一个公认标志，它可能提供新的治疗机会。然而，肾肿瘤重塑新陈代谢的分子机制仍然知之甚少。新的证据表明，肾癌中线粒体代谢途径的协调重构，包括三羧酸(TCA)循环和氧化磷酸化。这种重塑可能导致糖酵解的转变(即Warburg表型)。长期目标是确定肾癌改变新陈代谢的分子基础，并利用这一知识合理开发新的治疗方法，改善患者的预后。这项建议的目的是确定肾细胞癌重塑线粒体代谢的转录基础，并确定其在肿瘤发生中的作用。我们的中心假设是，转录因子PRDM16(PRD1-BF1-RIZ1同源结构域包含16)的表观遗传沉默促进了肾癌中的代谢开关，从而推动了肿瘤的发生。这一假设是基于申请人实验室的患者样本(正常肾脏、原发肿瘤和转移性肿瘤沉积)的初步数据，这些数据表明PRDM16缺失是这种恶性肿瘤中最显著的基因表达变化之一。拟议研究的基本原理是，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，基于强大的初步数据，将通过追求以下特定目标来验证：1)确定PRDM16调控TCA循环酶表达的转录基础；2)确定PRDM16缺失促进肿瘤代谢转变的机制；以及3)确定PRDM16在肾癌中缺失的表观遗传学基础以及这种缺失对肿瘤发生的贡献。这项拟议的研究意义重大，因为它将在靶向途径的背景下确定肾癌代谢转变的新驱动因素。这种方法是创新的，因为它将在表观基因组和肿瘤新陈代谢之间建立联系。归根结底，收集到的知识有可能提高晚期肾癌退伍军人的治疗效果，这是一种未得到满足的需求，对这种疾病的当代管理提出了挑战。

 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.