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

Georgios Batsios; Pavithra Viswanath; Elavarasan Subramani; Chloe Najac; Anne Marie Gillespie; Romelyn Delos Santos; Abigail R Molloy; Russell O Pieper; Sabrina M Ronen

doi:10.1038/s41598-019-47021-x

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

Sci Rep. 2019 Jul 19;9(1):10521. doi: 10.1038/s41598-019-47021-x.

Authors

Georgios Batsios¹, Pavithra Viswanath¹, Elavarasan Subramani¹, Chloe Najac¹, Anne Marie Gillespie¹, Romelyn Delos Santos¹, Abigail R Molloy¹, Russell O Pieper², Sabrina M Ronen^{3

4}

Affiliations

¹ Department of Radiology and Biomedical Imaging, Mission Bay Campus, 1700 4th Street, Byers Hall, University of California, 94158, San Francisco, CA, United States.
² Department of Neurological Surgery, Helen Diller Research Center, 1450 3rd Street, University of California, 94143, San Francisco, CA, United States.
³ 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.
⁴ 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.

Abstract

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. ¹H-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 ¹H-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.

Publication types

Research Support, N.I.H., Extramural

MeSH terms

Adaptor Proteins, Signal Transducing / antagonists & inhibitors
Animals
Astrocytes / metabolism
Brain Neoplasms / metabolism*
Brain Neoplasms / mortality
Cell Cycle Proteins / antagonists & inhibitors
Cell Line, Transformed
Glioma / metabolism*
Glioma / mortality
Glucose / metabolism
Glutamine / metabolism
Glutarates / metabolism*
Humans
Isocitrate Dehydrogenase / genetics*
Kaplan-Meier Estimate
Mice
Neoplasm Proteins / genetics*
Neoplasm Proteins / metabolism
Nuclear Magnetic Resonance, Biomolecular
Phosphatidylinositol 3-Kinases / metabolism*
Phosphorylation
Protein Processing, Post-Translational
Quinoxalines / pharmacology
Quinoxalines / therapeutic use
Ribosomal Protein S6 Kinases / metabolism
Signal Transduction
Sulfonamides / pharmacology
Sulfonamides / therapeutic use
TOR Serine-Threonine Kinases / antagonists & inhibitors
TOR Serine-Threonine Kinases / metabolism*
Xenograft Model Antitumor Assays

Substances

Adaptor Proteins, Signal Transducing
Cell Cycle Proteins
EIF4EBP1 protein, human
Glutarates
Neoplasm Proteins
Quinoxalines
Sulfonamides
XL765
Glutamine
alpha-hydroxyglutarate
Isocitrate Dehydrogenase
MTOR protein, human
Ribosomal Protein S6 Kinases
TOR Serine-Threonine Kinases
Glucose

Abstract

Publication types

MeSH terms

Substances

Grants and funding