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Abstract #0636

PI3K/mTOR inhibition of IDH1 mutant glioma leads to reduced 2HG production that is associated with increased survival

Georgios Batsios1, Pavithra Viswanath1, Anne Marie Gillespie1, Elavarasan Subramani1, Joanna J Phillips2, Russell O Pieper 2, and Sabrina M Ronen1

1Radiology and Biomedical Imaging, University of California, San Francisco, San Francisco, CA, United States, 2Neurological Surgery, University of California, San Francisco, San Francisco, CA, United States

Mutant IDH1 produces the oncometabolite 2HG, which drives tumorigenesis in low-grade gliomas. One potential therapeutic option for such gliomas is treatment with a PI3K/mTOR inhibitor. Using cell models genetically-engineered to express mutant IDH1, we observed that PI3K/mTOR inhibition induced a reduction in 2HG levels in treated cells and tumors, that was associated with reduced cell proliferation and enhanced animal survival. The drop in 2HG was due to a reduction in its synthesis from both glucose and glutamine. Our study identifies MRS-detectable metabolic alterations that could serve as indicators of response for mutant IDH1 glioma patients undergoing treatment with PI3K/mTOR inhibitors.

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