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

肾细胞癌(RCC)是我国男性和女性最常见的十种肿瘤之一。 美国。可悲的是，25%到30%的肾癌患者存在转移性疾病，并有5年的存活率 利率只有5%。目前对于局部晚期或转移性肾细胞癌的治疗选择很少。 本实验室对代谢产物的研究证实，疑似肿瘤代谢物L-2-羟基戊二酸(L-2HG)含量较高 患上肾癌。L-2HG在肾细胞癌中的积聚是由于L-2HG酶表达减少所致 脱氢酶(L2HGDH)。在RCC中，L2HGDH经常发生复制丢失。这种酶通常 将L-2HG还原为KREB循环中间体α-酮戊二酸(αKG)的功能。我们的实验室有 证明了肾癌细胞中L2HGDH的修复抑制了肿瘤的表型。 代谢物是在癌细胞中积聚的代谢物，如L-2HG，可以通过以下方式影响基因转录 竞争性抑制修改α和组蛋白甲基化的DNAKG依赖的酶。由于他们的高 癌细胞、肿瘤代谢物的丰富为个性化发展提供了一个可行的选择 肾癌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-2HG能抑制氨基酸生物合成相关基因的表达 这种缺失改变了高水平L-2HG肾癌细胞的营养需求。根据这些初步数据，我们 假设这些酶的丢失在肾细胞癌中表现出有针对性的代谢倾向。在目标1中，我们将 剖析L-2HG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可能性。通过我们的研究，我们希望发现小说， 代谢物驱动的癌症患者的新陈代谢方法。

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.