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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：
9608626
负责人：
Garrett Joseph Brinkley
金额：
$ 3.74万
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 2022-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9608626
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 Doctor of Philosophy 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 Protein Precursors Purines Radiolabeled Renal Cell Carcinoma Renal carcinoma Research Residencies Role Sampling Serine Signal Transduction Starvation Students 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 enantiomer experimental study histone methylation improved in vivo infrastructure development innovation knock-down men methyl group neoplastic cell novel novel strategies novel therapeutics 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。