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E-GEOD-45198 - An Inhibitor of Mutant IDH1 Delays Growth and Promotes Differentiation of Glioma Cells Methylation Data for Xenograft Samples

Status
Released on 4 April 2013, last updated on 22 April 2013
Organism
Homo sapiens
Samples (28)
Array (1)
Protocols (32)
Description
The recent discovery of mutations in metabolic enzymes has rekindled interest in harnessing the altered metabolism of cancer cells for cancer therapy. One potential drug target is isocitrate dehydrogenase 1 (IDH1) which is mutated in multiple human cancers. Here, we examine the role of mutant IDH1 in fully transformed cells with endogenous IDH1 mutations. A selective R132H-IDH1 inhibitor (AGI-5198) identified through a high-throughput screen dose-dependently blocked the ability of the mutant enzyme (mIDH1) to produce R-2-hydroxyglutarate (R-2HG). Under conditions of near complete R-2HG inhibition, the mIDH1 inhibitor induced demethylation of histone H3K9M3 and expression of genes associated with gliogenic differentiation. Blockade of mIDH1 impaired the growth of IDH1-mutant - but not IDH1-wildtype – glioma cells without appreciable changes in genome wide DNA methylation. These data suggest that mIDH1 may promote glioma growth through mechanisms beyond its well-characterized epigenetic effects. Xenograft experiments were carried out with treatment cohorts of vehicle, 150mg/kg/day, 450mg/kg/day. After the indicated tumors were harvested and genomic DNA was extracted and analyzed by the Illumina 450k Methylation array.
Experiment type
methylation profiling by array 
Contacts
Daniel Rohle <rohled@mskcc.org>, Daniel A Rohle, Ingo K Mellinghoff
MIAME
PlatformsProtocolsVariablesProcessedRaw
Files
Investigation descriptionE-GEOD-45198.idf.txt
Sample and data relationshipE-GEOD-45198.sdrf.txt
Processed data (1)E-GEOD-45198.processed.1.zip
Additional data (1)E-GEOD-45198.additional.1.zip
Array designA-GEOD-13534.adf.txt
Links