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

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.

• Authors: Georgios Batsios, Pavithra Viswanath, Elavarasan Subramani, Chloe Najac, Anne Marie Gillespie, Romelyn Delos Santos, Abigail R Molloy, Russell O Pieper, Sabrina M Ronen
• Journal: Scientific reports (Sci Rep) Vol. 9 Issue 1 Pg. 10521 (07 19 2019) ISSN: 2045-2322 [Electronic] England
• PMID: 31324855 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• 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

Topics

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