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.
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.
|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 14:1590-601|
|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|
|Sood, Anup; Miller, Alexandra M; Brogi, Edi et al. (2016) Multiplexed immunofluorescence delineates proteomic cancer cell states associated with metabolism. JCI Insight 1:|
|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|
|Ran, Leili; Sirota, Inna; Cao, Zhen et al. (2015) Combined inhibition of MAP kinase and KIT signaling synergistically destabilizes ETV1 and suppresses GIST tumor growth. Cancer Discov 5:304-15|
|Yoo, Barney; Ma, Kai; Zhang, Li et al. (2015) Ultrasmall dual-modality silica nanoparticle drug conjugates: Design, synthesis, and characterization. Bioorg Med Chem 23:7119-30|
|Prados, Michael D; Byron, Sara A; Tran, Nhan L et al. (2015) Toward precision medicine in glioblastoma: the promise and the challenges. Neuro Oncol 17:1051-63|
|Alexander, Brian M; Galanis, Evanthia; Yung, W K Alfred et al. (2015) Brain Malignancy Steering Committee clinical trials planning workshop: report from the Targeted Therapies Working Group. Neuro Oncol 17:180-8|
|Nichol, Donna; Mellinghoff, Ingo K (2015) PI3K pathway inhibition in GBMâ€”is there a signal? Neuro Oncol 17:1183-4|
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