Role of Oncometabolite L-2 Hydroxyglutarate in Reprogramming Renal Cell Carcinoma Metabolism

肾细胞癌（RCC）是世界上男性和女性最常见的十种肿瘤之一。 美国的不幸的是，25%至30%的RCC患者存在转移性疾病，5年生存率 率仅为5%。目前，局部晚期或转移性RCC的治疗选择很少。 我们实验室的代谢物研究确定了高水平的推定致癌代谢物L-2羟基戊二酸（L-2 HG） 在肾癌中。肾细胞癌中L-2 HG的积累是由于L-2 HG酶的表达减少 脱氢酶（L2 HGDH）。L2 HGDH在RCC中经常发生拷贝丢失。这种酶通常 其功能是将L-2 HG还原为α-酮戊二酸（αKG），一种Kreb循环中间体。我们的实验室 证实了肾癌细胞中L2 HGDH的恢复抑制肿瘤表型。 癌细胞中积累的代谢物，如L-2 HG，可以通过以下方式影响基因转录： 竞争性抑制修饰DNA和组蛋白甲基化的α KG依赖性酶。由于其高 癌细胞中的丰度，oncometectomy提供了一个可行的选择，为发展个性化 RCC以及其他癌症类型的治疗策略。我们实验室的初步研究 证明L-2 HG可以抑制参与氨基酸生物合成的基因的表达， 这种损失改变了高L-2 HG RCC细胞的营养需求。根据这些初步数据，我们 假设这些酶损失证明了RCC中可靶向的代谢倾向。在目标1中， 剖析L-2 HG抑制氨基酸生物合成的分子基础。在目标2中，我们将 评估针对这些发现进行治疗的潜力。通过我们的研究，我们希望找出新颖的， 代谢为基础的方法为癌症患者的癌代谢物驱动。

Renal cell carcinoma (RCC) is among the ten most common neoplasias for both men and women in the United States. Tragically, 25% to 30% of RCC patients present with metastatic disease, with 5-year survival rate of only 5%. There are currently very few therapeutic options for locally advanced or metastatic RCC. Metabolite studies by our lab identified high levels of the putative oncometabolite L-2 Hydroxyglutarate (L-2HG) in kidney cancer. Build up of L-2HG in RCC is due to reduced expression of the enzyme L-2HG dehydrogenase (L2HGDH). L2HGDH frequently undergoes copy loss in RCC. This enzyme normally functions to revert L-2HG back into alpha-ketoglutarate (αKG), a Kreb cycle intermediate. Our lab has demonstrated that restoration of L2HGDH in renal cancer cells suppresses tumor phenotypes. Oncometabolites, metabolites that build up in cancer cells, such as L-2HG, can affect gene transcription by competitively inhibiting αKG-dependent enzymes that modify DNA and histone methylation. Due to their high abundance in cancer cells, oncometabolites present a viable option for the development of personalized treatment strategies in RCC as well as other cancer types. Preliminary studies from our laboratory demonstrate that L-2HG can suppress the expression of genes involved in amino acid biosynthesis and that this loss alters nutrient requirements in high L-2HG RCC cells. Based on these preliminary data, we hypothesize that loss of these enzymes demonstrates a targetable metabolic liability in RCC. In aim 1, we will dissect the molecular underpinnings by which L-2HG can suppress amino acid biosynthesis. In aim 2, we will assess the potential to target these findings therapeutically. Through our studies, we hope to identify novel, metabolism-based approaches for patients with cancers that are oncometabolite driven.