Exploiting the vulnerabilities in mutant IDH gliomas

利用突变 IDH 神经胶质瘤的脆弱性

基本信息

批准号：
10588185
负责人：
Sheri L Holmen
金额：
$ 33.36万
依托单位：
UNIVERSITY OF UTAH
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-04-15 至 2025-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10588185
关键词：
Active Sites Adult Affect Amino Acids Anabolism Anchorage-Independent Growth Animal Model Arginine Astrocytes Binding Biology Brain Neoplasms Cell Respiration Cells Chemotherapy and/or radiation Chromosomes Citric Acid Cycle Clinic Consumption CpG Island Methylator Phenotype Cyclin-Dependent Kinase Inhibitor 2A DNA DNA Repair Decarboxylation Defect Dependence Development Diffuse Dioxygenases Disease Enterobacteria phage P1 Cre recombinase Enzymes Epigenetic Process Exhibits Family Genes Genetic Glioblastoma Glioma Gliomagenesis Glutamates Glutaminase Glutamine Glutathione Goals Growth Heterozygote Histidine Histologic Human Hypermethylation In Vitro Incidence Investigation Isocitrate Dehydrogenase Isocitrates Link Malignant Neoplasms Mediating Metabolism Missense Mutation Mixed Function Oxygenases Modality Modeling Mus Mutate Mutation NADP Oncogenes Oncogenic Operative Surgical Procedures Oxidative Phosphorylation Oxidative Stress Oxidative Stress Induction PTEN gene Patient-Focused Outcomes Persons Phenotype Platelet-Derived Growth Factor Primary Brain Neoplasms Production Prognosis Proliferating Proteins Radiation therapy Reporting Sampling TP53 gene Testing Therapeutic Time Transaminases Translations Treatment Efficacy Tumor Promotion United States Virus alpha ketoglutarate branched-chain-amino-acid transaminase chemotherapy clinical development clinically relevant combat cytotoxicity demethylation effectiveness evaluation efficacy evaluation gain of function histone demethylase human disease improved improved outcome in vivo in vivo Model inhibitor metabolic phenotype mitochondrial metabolism mouse model mutant mutant mouse model nestin protein new technology nondeletion type alpha-thalassemia/mental retardation syndrome novel novel therapeutics postnatal protein function tumor

Active Sites Adult Affect Amino Acids Anabolism Anchorage-Independent Growth Animal Model Arginine Astrocytes Binding Biology Brain Neoplasms Cell Respiration Cells Chemotherapy and/or radiation Chromosomes Citric Acid Cycle Clinic Consumption CpG Island Methylator Phenotype Cyclin-Dependent Kinase Inhibitor 2A DNA DNA Repair Decarboxylation Defect Dependence Development Diffuse Dioxygenases Disease Enterobacteria phage P1 Cre recombinase Enzymes Epigenetic Process Exhibits Family Genes Genetic Glioblastoma Glioma Gliomagenesis Glutamates Glutaminase Glutamine Glutathione Goals Growth Heterozygote Histidine Histologic Human Hypermethylation In Vitro Incidence Investigation Isocitrate Dehydrogenase Isocitrates Link Malignant Neoplasms Mediating Metabolism Missense Mutation Mixed Function Oxygenases Modality Modeling Mus Mutate Mutation NADP Oncogenes Oncogenic Operative Surgical Procedures Oxidative Phosphorylation Oxidative Stress Oxidative Stress Induction PTEN gene Patient-Focused Outcomes Persons Phenotype Platelet-Derived Growth Factor Primary Brain Neoplasms Production Prognosis Proliferating Proteins Radiation therapy Reporting Sampling TP53 gene Testing Therapeutic Time Transaminases Translations Treatment Efficacy Tumor Promotion United States Virus alpha ketoglutarate branched-chain-amino-acid transaminase chemotherapy clinical development clinically relevant combat cytotoxicity demethylation effectiveness evaluation efficacy evaluation gain of function histone demethylase human disease improved improved outcome in vivo in vivo Model inhibitor metabolic phenotype mitochondrial metabolism mouse model mutant mutant mouse model nestin protein new technology nondeletion type alpha-thalassemia/mental retardation syndrome novel novel therapeutics postnatal protein function tumor

展开

项目摘要

With incidence rates up to 80%, isocitrate dehydrogenase 1 (IDH1) is the most commonly mutated gene in grade II-III gliomas and secondary glioblastomas. Prior to its discovery in gliomas by Parsons et al. in 2008, this mutation had never before been linked to cancer. Subsequent studies have identified IDH1 and IDH2 mutations in several different tumor types suggesting that these genes are important players in cancer. The mechanism by which mutant IDH promotes tumor development has been under intense investigation and several key findings have significantly improved our understanding of the biology of this disease. IDH proteins function to generate reduced nicotinamide adenine dinucleotide phosphate (NADPH) from NADP+ by catalyzing the oxidative decarboxylation of isocitrate to α-ketoglutarate (α-KG). These mutations inhibit the native function of the enzyme and instead confer a gain-of-function phenotype resulting in the conversion of α- KG to 2-hydroxyglutarate (2-HG). 2-HG is a competitive inhibitor of multiple α-KG-dependent enzymes, including transaminases, histone demethylases, and the TET family of 5-methylcytosine hydroxylases, which mediate DNA demethylation. As a result, gliomas harboring mutations in IDH exhibit increased dependence on glutaminase, defects in DNA repair, and manifest a DNA hypermethylation phenotype. Mutant IDH also compromises the citric acid cycle, which results in an enhanced dependence on mitochondrial metabolism. Interestingly, the presence of an IDH mutation was found to be an independent marker for better prognosis and it was discovered that tumors harboring mutations in IDH are more sensitive to conventional chemotherapy and radiotherapy. As such, we hypothesize that tumors harboring mutations in IDH have multiple vulnerabilities that can be therapeutically exploited. However, evaluating these strategies has been hindered by the lack of appropriate in vivo models. To fill this void, we developed a mouse model of mutant IDH1-driven glioma that mimics the human disease genetically, functionally, and histologically. Our results support the hypothesis that mutant IDH1 is a bona fide glioma oncogene and provide the first in vivo evidence that it promotes gliomagenesis. The model we have developed is ideal for assessing rational therapeutic strategies to combat this disease. In this study, we propose to use human glioma cells and our novel mouse models to evaluate the sensitivity of these gliomas to DNA demethylating agents in combination with mutant IDH1 inhibitors, to exploit their dependence on glutamine metabolism, and to target their enhanced requirement for oxidative phosphorylation. Demonstration of therapeutic efficacy in our novel glioma mouse model will further support translation to the clinic and has the potential to significantly improve the outcome for patients with this deadly disease.

发病率高达80％，异位酸脱氢酶1（IDH1）是最常见的突变基因 II-III级神经胶质瘤和继发性胶质母细胞瘤。在帕森斯等人在神经胶质瘤中发现之前。 2008年，这种突变从未与癌症有关。随后的研究确定了IDH1和IDH2 几种不同肿瘤类型的突变表明这些基因是癌症的重要参与者。这突变体IDH促进肿瘤发育的机制一直在进行严格的研究和几个关键发现显着改善了我们对这种疾病生物学的理解。 IDH蛋白质从NADP+产生降低烟酰胺腺苷二核苷酸磷酸（NADPH）的功能催化异位酸的氧化脱羧为α-酮戊二酸（α-KG）。这些突变抑制了酶的天然功能和会议的功能获得表型，导致α-转化千克至2-羟基戊二酸（2-HG）。 2-HG是多种α-KG依赖性酶的竞争抑制剂，包括转氨酶，组蛋白脱甲基酶和5-甲基环肽羟化酶的TET家族，这些家族介导DNA脱甲基化。结果，在IDH暴露中含有突变的胶质瘤增加了对谷氨酰胺酶，DNA修复中的缺陷，表现出DNA高甲基化表型。突变的IDH也是如此损害柠檬酸周期，从而增强了对线粒体代谢的依赖性。有趣的是，发现存在IDH突变是更好预后和的独立标记有人发现，携带IDH突变的肿瘤对常规化学疗法更敏感和放射疗法。因此，我们假设携带IDH突变的肿瘤具有多种漏洞这可以从历史上探索。但是，由于缺乏合适的体内模型。为了填补这个空白，我们开发了一种突变体IDH1驱动神经胶质瘤的小鼠模型在遗传，功能和组织学上模仿人类疾病。我们的结果支持以下假设突变IDH1是一种真正的神经胶质瘤癌基因，并提供了第一个体内证据表明它促进神经胶质作用。我们开发的模型是评估合理治疗策略的理想选择这种疾病。在这项研究中，我们建议使用人神经胶质瘤细胞和新型小鼠模型来评估这些神经胶质瘤对DNA脱甲基剂的敏感性与突变IDH1抑制剂结合使用，以利用它们对谷氨酰胺代谢的依赖，并针对其增强的氧化需求磷酸化。在我们新颖的Glioma小鼠模型中的治疗效率的演示将进一步支持转化为诊所，并有可能显着改善该致命患者的结果疾病。