The Metabolic Pathogenesis of Chromophobe Renal Cell Carcinoma

嫌色肾细胞癌的代谢发病机制

基本信息

批准号：
10079018
负责人：
Elizabeth P Henske
金额：
$ 40.78万
依托单位：
BRIGHAM AND WOMEN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-01-15 至 2022-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10079018
关键词：
Address Adjuvant Anabolism BAY 54-9085 CRISPR interference CRISPR screen Cell Line Cell Proliferation Cells Chromophobe Renal Cell Carcinoma Chronic Citric Acid Cycle Clear Cell Clinical Data Data Set Disease Drug Screening Frequencies Gamma-glutamyl transferase Genes Genetic Genomics Glucose Glutamate-Cysteine Ligase Glutaminase Glutamine Glutathione Goals Human Impairment In Vitro Kidney Knowledge Lead Life Expectancy Link Metabolic Metabolic Pathway Metabolism Mitochondria Modeling Molecular Mutation Neoplasm Metastasis Nonmetastatic Oncogenic Oxidative Stress Oxidoreductase PTEN gene Pathogenesis Pathogenicity Pathway interactions Patients Pentosephosphate Pathway Pharmacology Phase Phenotype Recurrence Renal carcinoma Role Syndrome TP53 gene Testing The Cancer Genome Atlas Therapeutic Tissue Sample Tuberous sclerosis protein complex Tumorigenicity base biological adaptation to stress candidate identification driver mutation enzyme pathway exome sequencing exposure pathway in vitro testing in vivo innovation metabolic phenotype metabolomics novel novel therapeutic intervention targeted treatment therapeutic target transcriptome sequencing tumor tumorigenesis

项目摘要

Abstract This project is focused on metabolic reprogramming in chromophobe renal cell carcinoma (ChRCC). ChRCC accounts for 5% of all sporadic renal cancers and can also occur in genetic syndromes including Birt-Hogg- Dube' (BHD) and Tuberous Sclerosis Complex (TSC), both autosomal dominant disorders. There are currently no specific therapies for metastatic ChRCC, and life expectancy is estimated to be less favorable than for metastatic clear cell RCC, highlighting the potential clinical impact of this project Using metabolomic profiling of ChRCC compared with matched normal kidney, we have uncovered a striking decrease in intermediates of the gamma-glutamyl cycle, known as the glutathione salvage pathway. Consistent with this distinctive metabolic phenotype, we found that Gamma-glutamyl transferase 1 (GGT1), the key enzyme of this pathway, is expressed at >100-fold lower levels in ChRCC vs. normal kidney. Low GGT1 activity is predicted to result in lower utilization of exogenous glutathione, enhanced de novo glutathione synthesis, and increased oxidative stress. These and other data lead to our central hypothesis: metabolic reprogramming triggered by impairment of the glutathione salvage pathway is critical in the pathogenesis of ChRCC. A key translational corollary of this hypothesis is that ChRCC will be selectively sensitive to agents that inhibit glutathione biosynthesis and/or induce further oxidative stress. Aim 1. To determine the role of impairment of the glutathione salvage pathway in the pathogenesis and therapy of ChRCC. Aim 2. To determine the therapeutic impact of targeting glutathione biosynthetic pathways in ChRCC in vitro and in vivo. Aim 3. To identify molecular and metabolic determinants of the metastatic potential of ChRCC. If our hypotheses are correct, it will lead to a completely new pathogenic model for ChRCC, and to the identification of candidate therapeutic targets. Our long-term goal is to identify paradigm-shifting targeted therapeutic opportunities for patients with recurrent or metastatic ChRCC, for whom there are currently no proven therapeutic options.

抽象的该项目的重点是嫌色肾细胞癌（ChRCC）的代谢重编程。肾细胞癌占所有散发性肾癌的 5%，也可能发生在包括 Birt-Hogg 在内的遗传综合征中 Dube' (BHD) 和结节性硬化症 (TSC) 都是常染色体显性遗传疾病。目前有目前尚无针对转移性 ChRCC 的具体疗法，且预期寿命预计不如转移性 ChRCC 转移性透明细胞肾细胞癌，强调了该项目的潜在临床影响使用 ChRCC 与匹配的正常肾脏的代谢组学分析，我们发现了一个惊人的发现 γ-谷氨酰循环中间体的减少，称为谷胱甘肽补救途径。与这种独特的代谢表型一致，我们发现γ-谷氨酰转移酶 1 (GGT1) 该途径的关键酶在 ChRCC 中的表达水平比正常肾脏低 100 倍以上。低 GGT1 预计活性会导致外源性谷胱甘肽利用率降低，增强从头谷胱甘肽合成，并增加氧化应激。这些和其他数据引出了我们的中心假设：代谢由谷胱甘肽补救途径受损引发的重编程在以下疾病的发病机制中至关重要肾细胞癌。该假设的一个关键转化推论是 ChRCC 对药物选择性敏感抑制谷胱甘肽生物合成和/或诱导进一步的氧化应激。目的 1. 确定谷胱甘肽补救途径受损在发病机制中的作用和 ChRCC 的治疗。目标 2. 确定靶向谷胱甘肽生物合成途径对 ChRCC 的体外治疗效果和体内。目标 3. 确定 ChRCC 转移潜力的分子和代谢决定因素。如果我们的假设是正确的，这将导致 ChRCC 的全新致病模型，并导致确定候选治疗靶点。我们的长期目标是确定范式转变的目标复发性或转移性 ChRCC 患者的治疗机会，目前尚无针对这些患者的治疗机会经过验证的治疗选择。