Exploiting the vulnerabilities in mutant IDH gliomas

利用突变 IDH 神经胶质瘤的脆弱性

• 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
• 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

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（IDH 1）是最常见的突变基因，其发病率高达80%。 II-III级胶质瘤和继发性胶质母细胞瘤。在2008年Parsons等人在神经胶质瘤中发现它之前， 这种突变以前从未与癌症有关。随后的研究确定了IDH 1和IDH 2 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。的 突变体IDH促进肿瘤发展的机制一直在深入研究中， 几项重要发现大大提高了我们对这种疾病生物学的认识。IDH蛋白质 通过以下方式从NADP+产生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生成α-酮戊二酸（α-KG）。这些突变抑制了 酶的天然功能，而是赋予功能获得表型，导致α- KG转化为2-羟基戊二酸（2-HG）。2-HG是多种α-KG依赖性酶的竞争性抑制剂， 包括转氨酶、组蛋白脱甲基酶和5-甲基胞嘧啶羟化酶的泰特家族， 介导DNA去甲基化。因此，携带IDH突变的胶质瘤表现出对IDH的依赖性增加。 转氨酶，DNA修复缺陷，并表现出DNA超甲基化表型。突变IDH也 损害柠檬酸循环，这导致对线粒体代谢的依赖性增强。 有趣的是，IDH突变的存在被发现是更好预后的独立标志物， 发现IDH突变的肿瘤对常规化疗更敏感， 和放射治疗。因此，我们假设携带IDH突变的肿瘤具有多种脆弱性， 可以用于治疗然而，评估这些战略一直受到缺乏 合适的体内模型。为了填补这一空白，我们开发了一种突变IDH 1驱动的胶质瘤小鼠模型， 在基因上、功能上和组织学上模仿人类疾病。我们的研究结果支持这一假设， 突变IDH 1是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 胶质瘤形成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，我们建议使用人类胶质瘤细胞和我们的新小鼠模型来评估 这些神经胶质瘤对DNA去甲基化剂与突变IDH 1抑制剂组合的敏感性， 它们对谷氨酰胺代谢的依赖性，并针对它们对氧化的增强需求， 磷酸化在我们的新型胶质瘤小鼠模型中证明治疗效果将进一步支持 翻译到诊所，并有可能显着改善这种致命的患者的结果。 疾病