PMID- 31324855 OWN - NLM STAT- MEDLINE DCOM- 20201102 LR - 20211204 IS - 2045-2322 (Electronic) IS - 2045-2322 (Linking) VI - 9 IP - 1 DP - 2019 Jul 19 TI - PI3K/mTOR inhibition of IDH1 mutant glioma leads to reduced 2HG production that is associated with increased survival. PG - 10521 LID - 10.1038/s41598-019-47021-x [doi] LID - 10521 AB - 70-90% of low-grade gliomas and secondary glioblastomas are characterized by mutations in isocitrate dehydrogenase 1 (IDHmut). IDHmut produces the oncometabolite 2-hydroxyglutarate (2HG), which drives tumorigenesis in these tumors. The phosphoinositide-3-kinase (PI3K)/mammalian target of rapamycin (mTOR) pathway represents an attractive therapeutic target for IDHmut gliomas, but noninvasive indicators of drug target modulation are lacking. The goal of this study was therefore to identify magnetic resonance spectroscopy (MRS)-detectable metabolic biomarkers associated with IDHmut glioma response to the dual PI3K/(mTOR) inhibitor XL765. (1)H-MRS of two cell lines genetically modified to express IDHmut showed that XL765 induced a significant reduction in several intracellular metabolites including 2HG. Importantly, examination of an orthotopic IDHmut tumor model showed that enhanced animal survival following XL765 treatment was associated with a significant in vivo (1)H-MRS detectable reduction in 2HG but not with significant inhibition in tumor growth. Further validation is required, but our results indicate that 2HG could serve as a potential noninvasive MRS-detectable metabolic biomarker of IDHmut glioma response to PI3K/mTOR inhibition. FAU - Batsios, Georgios AU - Batsios G AD - Department of Radiology and Biomedical Imaging, Mission Bay Campus, 1700 4th Street, Byers Hall, University of California, 94158, San Francisco, CA, United States. FAU - Viswanath, Pavithra AU - Viswanath P AD - Department of Radiology and Biomedical Imaging, Mission Bay Campus, 1700 4th Street, Byers Hall, University of California, 94158, San Francisco, CA, United States. FAU - Subramani, Elavarasan AU - Subramani E AD - Department of Radiology and Biomedical Imaging, Mission Bay Campus, 1700 4th Street, Byers Hall, University of California, 94158, San Francisco, CA, United States. FAU - Najac, Chloe AU - Najac C AD - Department of Radiology and Biomedical Imaging, Mission Bay Campus, 1700 4th Street, Byers Hall, University of California, 94158, San Francisco, CA, United States. FAU - Gillespie, Anne Marie AU - Gillespie AM AD - Department of Radiology and Biomedical Imaging, Mission Bay Campus, 1700 4th Street, Byers Hall, University of California, 94158, San Francisco, CA, United States. FAU - Santos, Romelyn Delos AU - Santos RD AD - Department of Radiology and Biomedical Imaging, Mission Bay Campus, 1700 4th Street, Byers Hall, University of California, 94158, San Francisco, CA, United States. FAU - Molloy, Abigail R AU - Molloy AR AD - Department of Radiology and Biomedical Imaging, Mission Bay Campus, 1700 4th Street, Byers Hall, University of California, 94158, San Francisco, CA, United States. FAU - Pieper, Russell O AU - Pieper RO AD - Department of Neurological Surgery, Helen Diller Research Center, 1450 3rd Street, University of California, 94143, San Francisco, CA, United States. FAU - Ronen, Sabrina M AU - Ronen SM AD - Department of Radiology and Biomedical Imaging, Mission Bay Campus, 1700 4th Street, Byers Hall, University of California, 94158, San Francisco, CA, United States. sabrina.ronen@ucsf.edu. AD - Brain Tumor Research Center, Helen Diller Family Cancer Research Building, 1450 3rd Street, University of California, 94158, San Francisco, CA, United States. sabrina.ronen@ucsf.edu. LA - eng GR - R01 CA172845/CA/NCI NIH HHS/United States GR - R01 CA197254/CA/NCI NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural DEP - 20190719 PL - England TA - Sci Rep JT - Scientific reports JID - 101563288 RN - 0 (Adaptor Proteins, Signal Transducing) RN - 0 (Cell Cycle Proteins) RN - 0 (EIF4EBP1 protein, human) RN - 0 (Glutarates) RN - 0 (Neoplasm Proteins) RN - 0 (Quinoxalines) RN - 0 (Sulfonamides) RN - 0 (XL765) RN - 0RH81L854J (Glutamine) RN - 2889-31-8 (alpha-hydroxyglutarate) RN - EC 1.1.1.41 (Isocitrate Dehydrogenase) RN - EC 2.7.1.1 (MTOR protein, human) RN - EC 2.7.11.1 (Ribosomal Protein S6 Kinases) RN - EC 2.7.11.1 (TOR Serine-Threonine Kinases) RN - IY9XDZ35W2 (Glucose) SB - IM MH - Adaptor Proteins, Signal Transducing/antagonists & inhibitors MH - Animals MH - Astrocytes/metabolism MH - Brain Neoplasms/*metabolism/mortality MH - Cell Cycle Proteins/antagonists & inhibitors MH - Cell Line, Transformed MH - Glioma/*metabolism/mortality MH - Glucose/metabolism MH - Glutamine/metabolism MH - Glutarates/*metabolism MH - Humans MH - Isocitrate Dehydrogenase/*genetics MH - Kaplan-Meier Estimate MH - Mice MH - Neoplasm Proteins/*genetics/metabolism MH - Nuclear Magnetic Resonance, Biomolecular MH - Phosphatidylinositol 3-Kinases/*metabolism MH - Phosphorylation MH - Protein Processing, Post-Translational MH - Quinoxalines/pharmacology/therapeutic use MH - Ribosomal Protein S6 Kinases/metabolism MH - Signal Transduction MH - Sulfonamides/pharmacology/therapeutic use MH - TOR Serine-Threonine Kinases/antagonists & inhibitors/*metabolism MH - Xenograft Model Antitumor Assays PMC - PMC6642106 COIS- The authors declare no competing interests. EDAT- 2019/07/22 06:00 MHDA- 2020/11/03 06:00 PMCR- 2019/07/19 CRDT- 2019/07/21 06:00 PHST- 2018/11/22 00:00 [received] PHST- 2019/07/09 00:00 [accepted] PHST- 2019/07/21 06:00 [entrez] PHST- 2019/07/22 06:00 [pubmed] PHST- 2020/11/03 06:00 [medline] PHST- 2019/07/19 00:00 [pmc-release] AID - 10.1038/s41598-019-47021-x [pii] AID - 47021 [pii] AID - 10.1038/s41598-019-47021-x [doi] PST - epublish SO - Sci Rep. 2019 Jul 19;9(1):10521. doi: 10.1038/s41598-019-47021-x.