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：
9512773
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 2020-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9512773
关键词：
Acute Myelocytic Leukemia Affect Anabolism Analytical Chemistry Animal Model Architecture Behavior Biochemical Pathway Cancer Cell Growth Cancer cell line Carbon Cell Line Cell Respiration Cells Characteristics Chondrocytes Chondrosarcoma Citric Acid Cycle Clinic Clinical Computational algorithm Computing Methodologies Critical Pathways 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 Oxides 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 lipid biosynthesis metabolic abnormality assessment mitochondrial metabolism mutant neoplastic cell novel novel strategies primary bone cancer progenitor public health relevance response small hairpin RNA 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）：等酸脱氢酶1（IDH1）和IDH2中的体细胞突变经常发生在许多癌症中，包括神经胶质瘤，急性髓样白血病和软骨肉瘤。这些突变有助于通过（d）2-羟基氯甲酸酯oncometabolite的新形态产生肿瘤发生，但也损害了重要代谢途径的活性。我们的初步研究表明，在IDH1突变肿瘤中支持肿瘤生长的三羧酸（TCA）周期的临界功能在IDH1突变肿瘤中是功能障碍，并且该缺陷可以针对特异性地限制通过该基因型的癌细胞生长。在该项目中，我们将采用系统生物学方法和新颖的分析工具来确定IDH突变癌细胞中的其他代谢负债。这些方法将提供至关重要的新见解，以了解如何在癌细胞中尤其是在癌细胞，尤其是IDH突变型线中调节肿瘤细胞的氧化还原状态。我们假设TCA代谢和辅助因子依赖性氧化还原途径在IDH突变肿瘤中受到严重干扰，并且可以利用这些缺陷来选择性地减轻肿瘤的生长和存活。在AIM 1中，我们将使用13C MFA来表征通过致癌IDH1和IDH2突变对中央碳代谢的重编程。在AIM 2中，我们将确定具有致癌IDH1和IDH2细胞中胞质和线粒体NADPH的关键代谢来源。重要的是，体内微环境内肿瘤的代谢可能与观察到的体外观察到明显不同。在AIM 3中，我们将在异种移植模型中验证我们的代谢结果和靶标疗效。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制定和验证治疗策略，以利用IDH突变利用这些代谢缺陷。

项目成果

期刊论文数量（12）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Reverse engineering the cancer metabolic network using flux analysis to understand drivers of human disease.

DOI：
10.1016/j.ymben.2017.11.013
发表时间：
2018-01
期刊：
Metabolic engineering
影响因子：
8.4
作者：
Badur MG;Metallo CM
通讯作者：
Metallo CM

Oncogenic R132 IDH1 Mutations Limit NADPH for De Novo Lipogenesis through (D)2-Hydroxyglutarate Production in Fibrosarcoma Sells.

DOI：
10.1016/j.celrep.2018.09.074
发表时间：
2018-10-23
期刊：
Cell reports
影响因子：
8.8
作者：
Badur MG;Muthusamy T;Parker SJ;Ma S;McBrayer SK;Cordes T;Magana JH;Guan KL;Metallo CM
通讯作者：
Metallo CM

Metabolic consequences of oncogenic IDH mutations.