Exploiting Metabloic Defects in Tumors with Mutant IDH1 and IDH2

描述(申请人提供)：异柠檬酸脱氢酶1(IDH1)和异柠檬酸脱氢酶2(IDH2)的体细胞突变在许多癌症中频繁发生，包括胶质瘤、急性髓系白血病和软骨肉瘤。这些突变通过(D)2-羟基戊二酸代谢物的新构型产生帮助启动肿瘤的发生，但也损害了重要代谢途径的活性。我们的初步研究表明，在IDH1突变的肿瘤中，支持肿瘤在低氧下生长的三羧酸(TCA)循环的一个关键功能是功能障碍，这一缺陷可以被靶向特异性地限制具有该基因的癌细胞的生长。在这个项目中，我们将应用系统生物学方法和新的分析工具来确定IDH突变癌细胞的额外代谢倾向。这些方法将为线粒体新陈代谢和肿瘤细胞的氧化还原状态如何在癌细胞中调节提供关键的新见解，特别是IDH突变株。我们假设，在IDH突变的肿瘤中，TCA代谢和辅因子依赖的氧化还原途径受到严重干扰，这些缺陷可以被用来选择性地减轻肿瘤的生长和存活率。在目标1中，我们将使用13C MFA表征通过致癌的IDH1和IDH2突变对中心碳代谢的重新编程。在目标2中，我们将在具有IDH1和IDH2致癌基因的细胞中确定胞浆和线粒体NADPH的关键代谢来源。重要的是，肿瘤在体内微环境中的代谢可能与体外观察到的显著不同。在目标3中，我们将在异种移植模型中验证我们的代谢结果和靶向疗效。总的来说，从我们的代谢系统生物学方法中获得的信息将用于开发和验证利用IDH突变癌症中的这些代谢缺陷的治疗策略。

DESCRIPTION (provided by applicant): Somatic mutations in isocitrate dehydrogenase 1 (IDH1) and IDH2 occur frequently in a number of cancers, including glioma, acute myeloid leukemia, and chondrosarcoma. These mutations help initiate tumorigenesis via neomorphic production of the (D)2-hydroxyglutarate oncometabolite but also compromise the activity of important metabolic pathways. Our preliminary studies indicate that a critical function of the tricarboxylic acid (TCA) cycle that supports tumor growth under hypoxia is dysfunctional in IDH1 mutant tumors, and this defect can be targeted to specifically limit the growth of cancer cells with this genotype. In this project we will apply systems biology approaches and novel analytical tools to identify additional metabolic liabilities in IDH mutant cancer cells. These methods will provide crucial new insights into how mitochondrial metabolism and the redox state of tumor cells are regulated in cancer cells generally and IDH mutant lines in particular. We hypothesize that TCA metabolism and cofactor-dependent redox pathways are critically perturbed in IDH mutant tumors, and these defects can be exploited to selectively mitigate tumor growth and survival. In Aim 1 we will characterize the reprogramming of central carbon metabolism by oncogenic IDH1 and IDH2 mutations using 13C MFA. In Aim 2 we will identify critical metabolic sources of cytosolic and mitochondrial NADPH in cells with oncogenic IDH1 and IDH2. Importantly, the metabolism of tumors within the in vivo microenvironment may differ significantly from that observed in vitro. In Aim 3 we will validate our metabolic findings and target efficacy in xenograft models. Collectively, the information gained from our metabolic systems biology approach will be used to develop and validate therapeutic strategies that exploit these metabolic defects in cancer with IDH mutations.