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Exploiting Metabloic Defects in Tumors with Mutant IDH1 and IDH2

利用 IDH1 和 IDH2 突变的肿瘤代谢缺陷

基本信息

批准号：
8768400
负责人：
Christian Michael Metallo
金额：
$ 32.16万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-07-01 至 2019-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8768400
关键词：
Acute Myelocytic Leukemia Affect Anabolism Analytical Chemistry Animal Model Architecture Behavior Biochemical Pathway Bone neoplasms Cancer Cell Growth Cancer cell line Carbon Cell Line Cell Respiration Cells Characteristics Chondrocytes Chondrosarcoma Citric Acid Cycle Clinic Clinical Computational algorithm Computing Methodologies Cytosol Data Defect Engineering Enzymes Exhibits Fatty Acids Genetic Genotype Glioma Glucose Glutamine Growth Homeostasis Hypoxia In Vitro Isocitrate Dehydrogenase Isocitrates Isotopes Label Lesion Malignant Neoplasms Mass Spectrum Analysis Mediating Mesenchymal Differentiation Metabolic Metabolic Pathway Metabolism Methods Mitochondria Modeling Monitor Mus Mutate Mutation NADH NADP Natural regeneration Nature Normal Cell Oncogenic Oxidation-Reduction Oxidoreductase Pathway interactions Production Proliferating Role Scientist Somatic Mutation Source Survival Rate Systems Biology Techniques Therapeutic Tissues Tracer Tricarboxylic Acids Xenograft Model Xenograft procedure analytical tool cancer cell cell growth cellular engineering cofactor enzyme activity in vivo insight isocitrate lipid biosynthesis metabolic abnormality assessment mutant neoplastic cell novel novel strategies progenitor public health relevance response tumor tumor growth tumor metabolism tumorigenesis

项目摘要

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.

描述（由申请人提供）：异柠檬酸脱氢酶1（IDH 1）和IDH 2的体细胞突变经常发生在许多癌症中，包括神经胶质瘤、急性髓性白血病和软骨肉瘤。这些突变有助于通过（D）2-羟基戊二酸癌代谢产物的新形态产生启动肿瘤发生，但也损害了重要代谢途径的活性。我们的初步研究表明，在缺氧条件下支持肿瘤生长的三羧酸（TCA）循环的关键功能在IDH 1突变型肿瘤中功能失调，这种缺陷可以靶向特异性限制具有这种基因型的癌细胞的生长。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识别IDH突变癌细胞中的额外代谢负债。这些方法将为线粒体代谢和肿瘤细胞的氧化还原状态在癌细胞中的调节提供重要的新见解，特别是IDH突变株。我们假设TCA代谢和辅因子依赖性氧化还原途径在IDH突变型肿瘤中受到严重干扰，这些缺陷可以被利用来选择性地减轻肿瘤生长和存活。在目标1中，我们将使用13 C MFA表征致癌IDH 1和IDH 2突变对中心碳代谢的重编程。在目标2中，我们将鉴定具有致癌IDH 1和IDH 2的细胞中胞质和线粒体NADPH的关键代谢来源。重要的是，体内微环境中肿瘤的代谢可能与体外观察到的代谢显著不同。在目标3中，我们将在异种移植模型中验证我们的代谢发现和靶向疗效。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突变癌症中这些代谢缺陷的治疗策略。