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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要癌症中的代谢重编程是一个有吸引力的治疗靶点来源，因为它促进肿瘤生长以及通过酶的转移，这些酶原则上可以用小分子抑制。重编程是肾细胞癌 (RCC) 所固有的。事实上，很少有肿瘤与代谢有如此密切的联系。 RCC 紊乱，特别是透明细胞 RCC (ccRCC)，这通过以下方式显示：透明细胞表型，由脂质/糖原积累引起；由 ccRCC 特征事件直接代谢重编程， VHL 失活；以及观察到代谢酶的种系突变导致 RCC，但很少有其他原因靶向代谢重编程的两个主要障碍是缺乏对肾细胞癌的了解。患者的新陈代谢和缺乏经过验证的转化平台为了应对这些挑战，我们。在第 1 – 5 年执行了 5 项主要活动。首先，我们率先在术中输注 13C 标记的营养物质患者直接报告人类肾细胞癌代谢，其中揭示了葡萄糖抑制等其次，我们从机制上表明，抑制葡萄糖氧化是由于氧化不足。第三，我们确定了无添加剂、原位植入的患者肿瘤（肿瘤移植物、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，指定治疗方法策略，在 TG 模型和原发性人类肿瘤组织中对其进行测试，并推进最有希望的线索。第五，我们证明原发性 ccRCC 肿瘤和转移瘤都使用谷氨酰胺来维持氧化还原基于我们和其他相关人员的发现，平衡并生产必需的生物合成中间体。谷氨酰胺在癌症中的作用，开发了 CB-839 谷氨酰胺酶抑制剂，但 ccRCC 试验已取得结果。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。我们的新数据不仅解释了 CB-839 缺乏功效，而且还发现了新的机会。事实上，虽然 CB-839 通过靶向谷氨酰胺酶来抑制碳代谢，但谷氨酰胺也是一种干预措施。 RCC 中的氮源，通过酰胺基转移酶进行加工，CB-839 不会抑制该酶。初步数据显示，JHU-083 的泛谷氨酰胺抑制不仅有效地抑制酰胺转移酶反应，还显着阻止 ccRCC TG 生长，以促进有效的谷氨酰胺的生长。以临床为目标，在第 6-10 年，我们将追求以下目标 1. 探索的作用。酰胺转移酶介导对 CB-839 谷氨酰胺酶抑制剂的耐药性目标 2. 将 IDH 酶靶向作用于 CB-839 谷氨酰胺酶抑制剂。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。