Human """"""""low grade"""""""" gliomas have long been viewed as an exceptionally heterogenous group of tumors of the central nervous system. This view has been challenged by the recent discovery that the majority of these tumors harbor an identical missense mutation in the catalytic pocket of the metabolic enzyme isocitrate dehydrogenase (IDH). The mutant protein loses its normal enzymatic activity and gains the new ability to produce the """"""""oncometabolite"""""""" 2-hydroxyglutarate (2HG). 2HG is structurally similar to alpha-ketoglutarate (AKG), accumulates at high levels (>100-fold) in tumor tissue, and competitively inhibits the activity of AKG- dependent enzymes. This family of enzymes includes histone lysine demethylases, 5-methylcytosine hydroxylases likely involved in DNA demethylation, the HIF prolyl hydroxylase, and other enzymes with diverse functions. In high grade gliomas that have evolved from lower grade gliomas, IDH1 mutation is associated with a CpG island methylator phenotype (CIMP) and increased RNA levels of genes expressed during normal neuronal differentiation (the """"""""proneural"""""""" gene expression subgroup). While these observations point toward a unique molecular pathogenesis of IDH1-mutant glioma, no experimental evidence thus far has incriminated mutant IDH1 as the cause of CIMP or documented its role in glioma initiation or maintenance. Using experimental glioma models derived by my group, we recently uncovered that expression of mutant IDH1 is sufficient to trigger genome-wide DNA hypermethylation (Turcan et al., Nature, in press), induces the expression of the neuronal differentiation marker Tuj-1 (Lu et al., Nature, in press), and is required for the in- vivo growthof IDH1-mutant human glioma xenografts. These new findings provide the first direct evidence for a role of mutant IDH1 in gliomagenesis and provide an experimental angle for further mechanistic studies.
Aim 1 will dissect the precise temporal sequence of DNA and histone lysine methylation during the development of G-CIMP, as well as their reversibility in response to pharmacologic inhibition of the mutant enzyme.
Aim 2 will determine the effects of mutant IDH1 on differentiation potential and self-renewal in distinct cellular compartments within the neurogenic-gliogenic axis.
Aim 3 will identify the downstream target of 2HG-inhibition that promotes tumor maintenance. Results of our studies will shed light on mechanisms through which an """"""""oncometabolite"""""""" can regulate the molecular pathogenesis of cancer and refine our view of mutant IDH1 as a potential therapeutic target in human glioma.

Public Health Relevance

Mutations in the metabolic enzyme isocitrate dehydrogenase (IDH) were recently discovered in the majority of of human low grade gliomas. IDH1 mutations occur early during the growth of these tumors and may represent the molecular """"""""driver"""""""" of this disease. This project aims to understand how the mutant IDH1 enzyme contributes to the biology of human glioma and leverages insights and experimental models developed by my group.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
1R01NS080944-01
Application #
8422542
Study Section
Cancer Genetics Study Section (CG)
Program Officer
Fountain, Jane W
Project Start
2012-09-30
Project End
2017-05-31
Budget Start
2012-09-30
Budget End
2013-05-31
Support Year
1
Fiscal Year
2012
Total Cost
$411,029
Indirect Cost
$173,417
Name
Sloan-Kettering Institute for Cancer Research
Department
Type
DUNS #
064931884
City
New York
State
NY
Country
United States
Zip Code
10065
Miloushev, Vesselin Z; Granlund, Kristin L; Boltyanskiy, Rostislav et al. (2018) Metabolic Imaging of the Human Brain with Hyperpolarized 13C Pyruvate Demonstrates 13C Lactate Production in Brain Tumor Patients. Cancer Res 78:3755-3760
Dunphy, Mark P S; Harding, James J; Venneti, Sriram et al. (2018) In Vivo PET Assay of Tumor Glutamine Flux and Metabolism: In-Human Trial of 18F-(2S,4R)-4-Fluoroglutamine. Radiology 287:667-675
Graham, Nicholas A; Minasyan, Aspram; Lomova, Anastasia et al. (2017) Recurrent patterns of DNA copy number alterations in tumors reflect metabolic selection pressures. Mol Syst Biol 13:914
Oldrini, Barbara; Hsieh, Wan-Ying; Erdjument-Bromage, Hediye et al. (2017) EGFR feedback-inhibition by Ran-binding protein 6 is disrupted in cancer. Nat Commun 8:2035
Codega, Paolo; Mellinghoff, Ingo K (2017) Dissecting Glioma Invasiveness in a 3D-Organotypic Model. Trends Mol Med 23:776-777
Grommes, Christian; Pastore, Alessandro; Palaskas, Nicolaos et al. (2017) Ibrutinib Unmasks Critical Role of Bruton Tyrosine Kinase in Primary CNS Lymphoma. Cancer Discov 7:1018-1029
Clark, Owen; Yen, Katharine; Mellinghoff, Ingo K (2016) Molecular Pathways: Isocitrate Dehydrogenase Mutations in Cancer. Clin Cancer Res 22:1837-42
Hong, Candice Sun; Graham, Nicholas A; Gu, Wen et al. (2016) MCT1 Modulates Cancer Cell Pyruvate Export and Growth of Tumors that Co-express MCT1 and MCT4. Cell Rep 14:1590-1601
de la Fuente, Macarena I; Young, Robert J; Rubel, Jennifer et al. (2016) Integration of 2-hydroxyglutarate-proton magnetic resonance spectroscopy into clinical practice for disease monitoring in isocitrate dehydrogenase-mutant glioma. Neuro Oncol 18:283-90
Pentsova, Elena I; Shah, Ronak H; Tang, Jiabin et al. (2016) Evaluating Cancer of the Central Nervous System Through Next-Generation Sequencing of Cerebrospinal Fluid. J Clin Oncol 34:2404-15

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