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

肿瘤代谢物 L-2 羟基戊二酸在肾细胞癌代谢重编程中的作用

基本信息

批准号：
10224875
负责人：
Garrett Joseph Brinkley
金额：
$ 4.12万
依托单位：
UNIVERSITY OF ALABAMA AT BIRMINGHAM
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-08-01 至 2022-05-14
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10224875
关键词：
Affect Amino Acids Anabolism Antioxidants Back Biological Assay Cell Line Cell Proliferation Cells Critical Thinking DNA Methylation Data Dependence Development Diet Disease Doctor of Medicine Enzymes Epigenetic Process Fellowship Gene Expression Generations Genes Genetic Genetic Transcription Glioma Glucose Glycine Grant Growth Histones In Vitro Laboratories Lipids Lysine Malignant Epithelial Cell Malignant Neoplasms Mass Spectrum Analysis Metabolic Metabolism Metastatic Renal Cell Cancer Methods Methylation Molecular Mus Neoplasms Non-Essential Amino Acid Nucleic Acids Nutritional Requirements Oncogenic Oxidoreductase Pathway interactions Patients Phenotype Phosphoglycerate dehydrogenase Principal Investigator Proliferating Proteins Purines Radiolabeled Renal Cell Carcinoma Renal carcinoma Research Residencies Role Sampling Serine Signal Transduction Starvation Survival Rate Therapeutic Time Training Transcriptional Regulation United States Urologic Oncology Woman Xenograft procedure alpha ketoglutarate aminoacid biosynthesis base cancer cell cancer therapy cancer type cofactor dietary restriction doctoral student enantiomer experimental study histone methylation improved in vivo infrastructure development innovation knock-down men methyl group neoplastic cell novel novel strategies novel therapeutic intervention overexpression personalized medicine restoration skills small hairpin RNA success therapeutic target transcriptome transcriptome sequencing treatment strategy tumor uptake urologic

项目摘要

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.

肾细胞癌（RCC）是男性和女性最常见的十种肿瘤之一美国。悲惨的是，25% 至 30% 的 RCC 患者出现转移性疾病，但生存期为 5 年率仅为5%。目前针对局部晚期或转移性肾细胞癌的治疗选择很少。我们实验室的代谢研究发现高水平的假定致癌代谢物 L-2 羟基戊二酸 (L-2HG) 在肾癌中。 RCC 中 L-2HG 的积累是由于 L-2HG 酶表达减少所致脱氢酶（L2HGDH）。 L2HGDH 在 RCC 中经常发生复制丢失。这种酶通常其功能是将 L-2HG 恢复为 α-酮戊二酸 (αKG)，一种克雷布循环中间体。我们实验室有证明肾癌细胞中 L2HGDH 的恢复可抑制肿瘤表型。肿瘤代谢物，即在癌细胞中积累的代谢物，例如 L-2HG，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 αKG 依赖性酶。由于他们的高癌细胞中丰富的肿瘤代谢物为个性化药物的开发提供了可行的选择 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-2HG 可以抑制参与氨基酸生物合成的基因的表达，并且这种损失改变了高 L-2HG RCC 细胞的营养需求。根据这些初步数据，我们假设这些酶的损失表明肾细胞癌中存在可靶向的代谢倾向。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潜力。通过我们的研究，我们希望发现新颖的、针对由代谢物驱动的癌症患者的基于代谢的方法。