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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：
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）：异柠檬酸脱氢酶1 （IDH1）和IDH2的体细胞突变经常发生在许多癌症中，包括胶质瘤、急性髓性白血病和软骨肉瘤。这些突变通过(D)2-羟戊二酸肿瘤代谢物的新形态产生帮助启动肿瘤发生，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）循环的一个关键功能在IDH1突变肿瘤中是功能失调的，这一缺陷可以被靶向以特异性地限制具有该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确定IDH突变癌细胞的额外代谢负荷。这些方法将为研究线粒体代谢和肿瘤细胞氧化还原状态如何在癌细胞中，特别是IDH突变系中受到调节提供重要的新见解。我们假设TCA代谢和辅助因子依赖的氧化还原途径在IDH突变肿瘤中受到严重干扰，这些缺陷可以被利用来选择性地减缓肿瘤的生长和存活。在目的1中，我们将使用13C MFA表征由致癌IDH1和IDH2突变引起的中心碳代谢重编程。在Aim 2中，我们将在具有致癌性IDH1和IDH2的细胞中确定细胞质和线粒体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在体外观察到的有很大不同。在Aim 3中，我们将在异种移植模型中验证我们的代谢发现和靶疗效。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这些代谢缺陷的IDH突变癌症的治疗策略。

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

Loss of succinate dehydrogenase activity results in dependency on pyruvate carboxylation for cellular anabolism.

DOI：
10.1038/ncomms9784
发表时间：
2015-11-02
期刊：
Nature communications
影响因子：
16.6
作者：
Lussey-Lepoutre C;Hollinshead KE;Ludwig C;Menara M;Morin A;Castro-Vega LJ;Parker SJ;Janin M;Martinelli C;Ottolenghi C;Metallo C;Gimenez-Roqueplo AP;Favier J;Tennant DA
通讯作者：
Tennant DA

Metabolic consequences of oncogenic IDH mutations.

DOI：
10.1016/j.pharmthera.2015.05.003
发表时间：
2015-08
期刊：
PHARMACOLOGY & THERAPEUTICS
影响因子：
13.5
作者：
Parker, Seth J.;Metallo, Christian M.
通讯作者：
Metallo, Christian M.

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

Tracing insights into human metabolism using chemical engineering approaches.