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：
10374107
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 2024-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10374107
关键词：
Active Sites Adult Affect Amino Acids Anabolism Anchorage-Independent Growth Animal Model Arginine Astrocytes Binding Biology Brain Neoplasms Cell Respiration Cells 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 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 PTEN gene Patient-Focused Outcomes Persons Phenotype Platelet-Derived Growth Factor Primary Brain Neoplasms Production Prognosis Proteins Radiation Radiation therapy Reporting Sampling TP53 gene Testing Therapeutic Time Transaminases Translations Treatment Efficacy 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

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.

异柠檬酸脱氢酶 1 (IDH1) 的发病率高达 80%，是最常见的突变基因。 2008 年 Parsons 等人在神经胶质瘤中发现了 II-III 级胶质瘤和继发性胶质母细胞瘤。此突变此前从未与癌症相关。随后的研究已确定 IDH1 和 IDH2。几种不同肿瘤类型的突变表明这些基因在癌症中发挥着重要作用。突变IDH促进肿瘤发展的机制已得到深入研究和一些重要的发现极大地提高了我们对这种疾病的生物学的理解。通过 NADP+ 生成还原型烟酰胺腺嘌呤二核苷酸磷酸 (NADPH) 催化异柠檬酸氧化脱羧为 α-酮戊二酸 (α-KG)。酶的天然功能，而是赋予功能获得表型，导致 α- 的转化 KG 转化为 2-羟基戊二酸 (2-HG)，是多种 α-KG 依赖性酶的竞争性抑制剂。包括转氨酶、组蛋白去甲基酶和 5-甲基胞嘧啶羟化酶 TET 家族，因此，携带 IDH 突变的神经胶质瘤表现出对 DNA 去甲基化的依赖性增加。谷氨酰胺酶、DNA 修复缺陷以及 DNA 高甲基化表型。损害柠檬酸循环，导致对线粒体代谢的依赖性增强。提示，IDH 突变的存在被发现是更好预后的独立标志物，研究发现，携带 IDH 突变的肿瘤对常规化疗更敏感因此，我们发现携带 IDH 突变的肿瘤具有多种脆弱性。然而，由于缺乏这些策略，评估这些策略受到了阻碍。为了填补这一空白，我们开发了突变 IDH1 驱动的神经胶质瘤小鼠模型。从基因、功能和组织学角度模拟人类疾病，我们的结果支持这样的假设：突变体 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我们开发的模型非常适合评估对抗神经胶质瘤的合理治疗策略。在这项研究中，我们建议使用人类神经胶质瘤细胞和我们的新型小鼠模型来评估这种疾病。这些神经胶质瘤对 DNA 去甲基化剂与突变 IDH1 抑制剂联合使用的敏感性，以利用他们对谷氨酰胺代谢的依赖，并针对他们对氧化的增强需求在我们的新型神经胶质瘤小鼠模型中证明治疗效果将进一步支持。转化为临床，有可能显着改善患有这种致命疾病的患者的治疗结果疾病。