The Metabolic Pathogenesis of Chromophobe Renal Cell Carcinoma

嫌色肾细胞癌的代谢发病机制

• 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
• 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

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.

摘要 该项目的重点是在嫌色肾细胞癌（ChRCC）的代谢重编程。ChRCC 占所有散发性肾癌的5%，也可发生在遗传综合征中，包括Birt-Hogg- Dube'（BHD）和硬化症（TSC），两者都是常染色体显性遗传病。目前有 没有针对转移性ChRCC的特异性疗法，估计预期寿命不如转移性ChRCC。 转移性透明细胞肾细胞癌，突出了该项目的潜在临床影响 使用ChRCC与匹配的正常肾脏相比的代谢组学分析，我们发现了一个惊人的 γ-谷氨酰循环（称为谷胱甘肽补救途径）的中间产物减少。 与这种独特的代谢表型一致，我们发现γ-谷氨酰转移酶1（GGT 1）， 该途径的关键酶在ChRCC中的表达水平比正常肾脏低>100倍。低GGT 1 预计活性会导致外源性谷胱甘肽的利用率降低， 合成和增加的氧化应激。这些和其他数据导致我们的中心假设：代谢 由谷胱甘肽补救途径受损引发的重编程在 ChRCC。这一假设的一个关键的翻译推论是，ChRCC将选择性地对药物敏感 其抑制谷胱甘肽生物合成和/或诱导进一步氧化应激。 目标1.确定谷胱甘肽补救途径受损在发病机制中的作用， 治疗ChRCC。 目标2.确定体外靶向谷胱甘肽生物合成途径对ChRCC的治疗作用 和体内。 目标3.确定ChRCC转移潜能的分子和代谢决定因素。 如果我们的假设是正确的，这将导致一个全新的致病模式，为ChRCC，并为 候选治疗靶点的鉴定。我们的长期目标是确定有针对性的范式转变 复发性或转移性ChRCC患者的治疗机会，目前没有 经过验证的治疗方案。