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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