Exploiting the vulnerabilities in mutant IDH gliomas

异柠檬酸脱氢酶1(IDH1)是人类最常见的基因突变，发病率高达80%。 II-III级胶质瘤和继发性胶质母细胞瘤。在Parsons等人在胶质瘤中发现它之前。二零零八年， 这种突变以前从未被认为与癌症有关。随后的研究发现了IDH1和IDH2 几种不同肿瘤类型的突变表明这些基因在癌症中起着重要作用。这个 突变型idh促进肿瘤发生的机制正在深入研究中。 几个关键的发现极大地提高了我们对这种疾病生物学的理解。IDH蛋白 通过以下途径从NADP+生成还原型烟酰胺腺嘌呤二核苷酸磷酸(NADPH)的功能 催化异柠檬酸氧化脱羧制α-酮戊二酸(α-KG)。这些突变抑制了 酶的天然功能，而不是赋予功能获得的表型，导致α- Kg至2-羟基戊二酸(2-HG)。2-HG是多种α-KG依赖酶的竞争性抑制物， 包括转氨酶、组蛋白去甲基酶和Tet家族的5-甲基胞嘧啶羟基酶，它们 介导DNA去甲基化。因此，携带IDH突变的胶质瘤表现出对 谷氨酰胺酶，DNA修复缺陷，表现为DNA高甲基化表型。突变体IDH也 破坏柠檬酸循环，导致对线粒体新陈代谢的依赖增强。 有趣的是，IDH突变的存在被发现是预后更好和 研究发现，携带IDH基因突变的肿瘤对常规化疗更敏感。 和放射治疗。因此，我们假设含有IDH突变的肿瘤具有多个易感性。 可以在治疗上加以利用。然而，对这些战略的评估因缺乏 合适的活体模型。为了填补这一空白，我们开发了一种突变的IDH1驱动的胶质瘤小鼠模型 从基因、功能和组织学上模仿人类疾病。我们的结果支持这样的假设 突变的IDH1是一种真正的胶质瘤癌基因，并提供了第一个体内证据表明它促进了 神经胶质瘤形成。我们开发的模型是评估对抗的合理治疗策略的理想选择 这种病。在这项研究中，我们建议使用人类胶质瘤细胞和我们的新的小鼠模型来评估 这些胶质瘤对DNA去甲基化药物和突变的IDH1抑制剂的敏感性，以开发 他们对谷氨酰胺代谢的依赖，并针对他们增强的氧化需求 磷酸化。在我们的新的胶质瘤小鼠模型中的治疗效果的证明将进一步支持 转化到临床上，有可能显著改善这种致命疾病患者的预后 疾病。

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.