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.

抽象的 该项目的重点是铬虫肾细胞癌（CHRCC）中的代谢重编程。 CHRCC 占所有零星肾脏癌的5％，也可能发生在包括Birt-Hogg-在内的遗传综合征中 杜贝（BHD）和结节性硬化症复合物（TSC），两种常染色体显性疾病。目前有 没有针对转移性CHCC的具体疗法，预期寿命估计不如比 转移性透明细胞RCC，强调了该项目的潜在临床影响 与匹配的正常肾脏相比，使用CHRC的代谢组分析，我们发现了惊人的 γ-谷氨酰基循环的中间体的减少，称为谷胱甘肽拯救途径。 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与正常肾脏中的水平低于100倍。低ggt1 预计活性会导致较低的外源谷胱甘肽的利用，从而增强了谷胱甘肽 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 通过谷胱甘肽打捞途径损害触发的重编程对于在发病机理中至关重要 CHRCC。该假设的关键翻译推论是CHRCC将对代理有选择敏感 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。确定谷胱甘肽打捞途径在发病机理和 Chrcc的治疗。 目标2。确定靶向靶向谷胱甘肽生物合成途径在CHRCC体外的治疗影响 和体内。 目的3。确定CHRC的转移潜力的分子和代谢决定因素。 如果我们的假设正确，它将导致CHRC的全新致病模型，并导致 识别候选治疗靶标。我们的长期目标是确定针对目标的范式 重复或转移性CHRC的患者的治疗机会，目前没有 经过验证的治疗选择。