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

项目摘要 癌症中的代谢重新编程是一个有吸引力的治疗靶点，因为它促进了肿瘤的生长 以及通过原则上可以被小分子抑制的酶进行转移。新陈代谢 重编程是肾细胞癌(RCC)固有的现象。事实上，很少有肿瘤与新陈代谢有如此密切的联系 无序排列为RCC，尤其是清除细胞RCC(CcRCC)。这表现为：透明细胞表型， 这是由脂质/糖原积累引起的；通过ccRCC签名事件直接代谢重编程， VHL失活；以及观察到代谢酶的胚系突变导致RCC，但很少有其他原因 肿瘤类型。靶向代谢再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有效的翻译平台。为了应对这些挑战，我们 在1-5年间执行了5项主要活动。首先，我们开创性地在术中输注13C标记的营养物质 患者直接报告人类的RCC新陈代谢，其中揭示了葡萄糖被抑制 氧化。第二，我们从机理上证明，葡萄糖氧化被抑制是由于氧化不足。 磷酸化。第三，我们确定无添加剂的原位植入的患者肿瘤(肿瘤移植， TG)是研究人肾细胞癌代谢的有效模型。第四，我们建立了体内代谢实验室， 一种创新的翻译平台，用于检测人类肿瘤的代谢重新编程，提名治疗 策略，在TG模型和原代人类肿瘤组织中测试它们，并提出最有希望的线索。 第五，我们证明了原发肾细胞癌和转移肾细胞癌都使用谷氨酰胺来维持氧化还原。 平衡和生产必要的生物合成中间体。以我们和其他牵连的人的发现为基础 癌症中的谷氨酰胺，CB-839谷氨酰胺酶抑制剂被开发出来。然而，ccRCC试验的结果 太令人失望了。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缺乏疗效，而且还发现了新的机会 干预。事实上，虽然CB-839通过靶向谷氨酰胺酶抑制碳代谢，但谷氨酰胺也是一种 RCC中的氮源，通过氨基转移酶处理，CB-839不抑制氨基转移酶。在……里面 初步数据显示，泛谷氨酰胺抑制用JHU-083不仅能有效抑制 氨基转移酶反应，也显著抑制ccRCC TG的生长。提高有效谷氨酰胺 以临床为目标，在6-10年，我们将追求以下目标。目标1.探讨 氨基转移酶在介导对CB-839谷氨酰胺酶抑制剂耐药性中的作用。目标2.以IDH酶为靶点 最大限度地阻断谷氨酰胺。目的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。

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.