Project 2: Defining Targetable Metabolic Dependencies in Human Renal Cell Carcinoma

项目 2：定义人类肾细胞癌的靶向代谢依赖性

• 批准号: 10708840
• 负责人: RALPH J DEBERARDINIS
• 金额: $ 33.93万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-08-01 至 2027-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10708840
• 关键词: Address; Bypass; Carbon; Cathepsins; Cell physiology; Cells; Citric Acid Cycle; Clear Cell; Clear cell renal cell carcinoma; Clinic; Collaborations; Cytotoxic T-Lymphocytes; Data; Dependence; Drug Targeting; Enzymes; Equilibrium; Event; Failure; Generations; Germ-Line Mutation; Glucose; Glutaminase; Glutamine; Glycogen; Growth; Human; Immune; Immunocompetent; Implant; Infusion procedures; Intervention; Knowledge; Label; Link; Lipids; Malignant Neoplasms; Mediating; Medical center; Metabolic; Metabolic Pathway; Metabolism; Mitochondria; Modeling; Mus; Neoplasm Metastasis; Nitrogen; Non-Malignant; Nutrient; Oxidation-Reduction; Oxidative Phosphorylation Deficiency; Pathway interactions; Patients; Pharmacologic Substance; Phenotype; Predisposition; Process; Reaction; Renal Cell Carcinoma; Renal carcinoma; Reporting; Resistance; Role; Source; Testing; Texas; Therapeutic; Translating; Tumor Promotion; Tumor Tissue; Universities; cell type; drug development; genetic approach; in vivo; inhibitor; innovation; insight; metabolomics; mouse model; neoplastic cell; next generation; nitrogen metabolism; novel; novel strategies; oxidation; small molecule; therapeutic target; treatment response; tumor; tumor growth; tumor metabolism; tumor microenvironment; tumorigenesis

Project Summary Metabolic reprogramming in cancer is an attractive source of therapeutic targets because it fuels tumor growth and metastasis through enzymes that are in principle amenable to inhibition with small molecules. Metabolic reprogramming is intrinsic to renal cell carcinoma (RCC). In fact, few tumors are as profoundly linked to metabolic derangement as RCC and in particular, clear cell RCC (ccRCC). This is shown by: the clear cell phenotype, which arises from lipid/glycogen accumulation; direct metabolic reprogramming by the ccRCC signature event, VHL inactivation; and the observation that germline mutations in metabolic enzymes cause RCC, but few other tumor types. The two main barriers to targeting metabolic reprograming are the lack of knowledge about RCC metabolism in patients and the absence of validated translational platforms. To address these challenges, we executed 5 major activities in Years 1 – 5. First, we pioneered intraoperative infusions of 13C-labeled nutrients in patients to directly report on RCC metabolism in humans, which revealed, among others, suppressed glucose oxidation. Second, we showed, mechanistically, that suppressed glucose oxidation is due to deficient oxidative phosphorylation. Third, we determined that additive-free, orthotopically implanted, patient tumors (tumorgrafts, TG) are valid models to study human RCC metabolism. Fourth, we established the In Vivo Metabolism Lab, an innovative translational platform to detect metabolic reprogramming in human tumors, nominate therapeutic strategies, test them in TG models and primary human tumor tissue, and advance the most promising leads. Fifth, we demonstrated that both primary ccRCC tumors and metastases use glutamine to maintain redox balance and produce essential biosynthetic intermediates. Building upon discoveries by us and others implicating glutamine in cancer, the CB-839 glutaminase inhibitor was developed. However, results in ccRCC trials have been disappointing. One possible explanation is that glutaminase is only one of several enzymes that catabolize glutamine. Our new data not only explain CB-839 lack of efficacy, but also identify new opportunities for intervention. Indeed, while CB-839 inhibits carbon metabolism by targeting glutaminase, glutamine is also a source of nitrogen in RCC, which is processed via amidotransferases, which are not inhibited by CB-839. In preliminary data, we show that pan-glutamine inhibition with JHU-083 not only effectively inhibits amidotransferase reactions, but also significantly blocks ccRCC TG growth. To advance effective glutamine targeting to the clinic, in Years 6 – 10, we will pursue the following Aims. Aim 1. Probing the role of amidotransferases in mediating resistance to CB-839 glutaminase inhibitor. Aim 2. Targeting IDH enzymes to maximize glutamine blockade. Aim 3. To maximize the impact of glutamine targeting by leveraging the tumor microenvironment using next-generation models.

项目摘要 癌症的代谢重编程是治疗靶标的有吸引力的来源 和通过小分子抑制的酶通过酶的转移。代谢 重编程是肾细胞癌（RCC）的固有的。实际上，很少有肿瘤与代谢有直接联系 演变为RCC，尤其是Clear Cell RCC（CCRCC）。这是通过：清晰的细胞表型， 由脂质/糖原积累引起的；通过CCRCC签名事件直接代谢重编程， VHL失活；并且观察到代谢酶中种系突变引起RCC，但很少有其他 肿瘤类型。靶向代谢重编程的两个主要障碍是缺乏有关RCC的知识 患者的代谢和缺乏经过验证的翻译平台。为了应对这些挑战，我们 在1 - 5年内执行了5项主要活动。首先，我们在13c标记的营养素中开创了术中输注。 患者直接报告人类的RCC代谢，这表明抑制了葡萄糖 氧化。其次，我们机械地表明，抑制葡萄糖氧化是由于氧化不足引起的 磷酸化。第三，我们确定无添加剂，原位植入的患者肿瘤（肿瘤植物， TG）是研究人RCC代谢的有效模型。第四，我们建立了体内代谢实验室， 一个创新的转化平台，用于检测人类肿瘤中的代谢重编程，提名治疗 策略，在TG模型和原发性人类肿瘤组织中测试它们，并推进最有希望的铅。 第五，我们证明了原发性CCRCC肿瘤和转移都使用谷氨酰胺维持氧化还原 平衡并产生必需的生物合成中间体。建立在我们和其他人的发现的基础上 谷氨酰胺在癌症中，开发了CB-839谷氨酰胺酶抑制剂。但是，CCRCC试验的结果具有 令人失望。一种可能的解释是，谷氨酰胺酶只是分解代谢的几种酶之一 谷氨酰胺。我们的新数据不仅解释了CB-839缺乏效率，而且还确定了新的机会 干涉。确实，尽管CB-839通过靶向谷氨酰胺抑制碳代谢，但谷氨酰胺也是一种 RCC中的氮来源，该氮是通过氧化转移酶处理的，该氮未受CB-839抑制。在 初步数据，我们显示JHU-083的泛谷氨酰胺抑制不仅有效地抑制 氧化转移酶的反应，但也显着阻止了CCRCC TG的增长。提高有效的谷氨酰胺 针对诊所的目标，在6至10年中，我们将追求以下目标。目标1。探测角色 在介导对CB-839谷氨酰胺酶抑制剂的耐药性方面的氧化转移酶。目标2。将IDH酶靶向 最大化谷氨酰胺封锁。目标3。通过利用肿瘤来最大化谷氨酰胺靶向的影响 使用下一代模型的微环境。