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.
Cancer cells require large quantities of energy and cellular building blocks for growth and survival. Intriguingly, mutations in the machinery used to generate this energy occur frequently in some cancers, leading to potential defects in the survival response of some tumors. In this project we will study how these metabolic defects can be exploited in tumors with such mutations using a combination of analytical chemistry and computational methods, validating our results in animal models.
|Badur, Mehmet G; Muthusamy, Thangaselvam; Parker, Seth J et al. (2018) Oncogenic R132 IDH1 Mutations Limit NADPH for De Novo Lipogenesis through (D)2-Hydroxyglutarate Production in Fibrosarcoma Cells. Cell Rep 25:1680|
|McBrayer, Samuel K; Mayers, Jared R; DiNatale, Gabriel J et al. (2018) Transaminase Inhibition by 2-Hydroxyglutarate Impairs Glutamate Biosynthesis and Redox Homeostasis in Glioma. Cell 175:101-116.e25|
|Badur, Mehmet G; Metallo, Christian M (2018) Reverse engineering the cancer metabolic network using flux analysis to understand drivers of human disease. Metab Eng 45:95-108|
|Sanchez-Gurmaches, Joan; Tang, Yuefeng; Jespersen, Naja Zenius et al. (2018) Brown Fat AKT2 Is a Cold-Induced Kinase that Stimulates ChREBP-Mediated De Novo Lipogenesis to Optimize Fuel Storage and Thermogenesis. Cell Metab 27:195-209.e6|
|Zhao, Dongxin; Badur, Mehmet G; Luebeck, Jens et al. (2018) Combinatorial CRISPR-Cas9 Metabolic Screens Reveal Critical Redox Control Points Dependent on the KEAP1-NRF2 Regulatory Axis. Mol Cell 69:699-708.e7|
|Wortham, Matthew; Benthuysen, Jacqueline R; Wallace, Martina et al. (2018) Integrated In Vivo Quantitative Proteomics and Nutrient Tracing Reveals Age-Related Metabolic Rewiring of Pancreatic ? Cell Function. Cell Rep 25:2904-2918.e8|
|Sessions, Ayla O; Min, Peter; Cordes, Thekla et al. (2018) Preserved cardiac function by vinculin enhances glucose oxidation and extends health- and life-span. APL Bioeng 2:|
|Jin, Lingtao; Chun, Jaemoo; Pan, Chaoyun et al. (2018) The PLAG1-GDH1 Axis Promotes Anoikis Resistance and Tumor Metastasis through CamKK2-AMPK Signaling in LKB1-Deficient Lung Cancer. Mol Cell 69:87-99.e7|
|Wallace, Martina; Green, Courtney R; Roberts, Lindsay S et al. (2018) Enzyme promiscuity drives branched-chain fatty acid synthesis in adipose tissues. Nat Chem Biol 14:1021-1031|
|Badur, Mehmet G; Muthusamy, Thangaselvam; Parker, Seth J et al. (2018) Oncogenic R132 IDH1 Mutations Limit NADPH for De Novo Lipogenesis through (D)2-Hydroxyglutarate Production in Fibrosarcoma Sells. Cell Rep 25:1018-1026.e4|
Showing the most recent 10 out of 30 publications