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

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

doi:10.1038/s41598-019-47021-x

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 vivo1H-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.

Highlights

Wild type IDH1 catalyzes the oxidative decarboxylation of isocitrate to α-ketoglutarate (α-KG)
XL765 treatment inhibits 4E-BP1 and S6K phosphorylation downstream of phosphatidylinositol 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) signaling in low-grade gliomas
NHAIDHmut cells were treated with 32 μM XL765 for 72 h leading to 55.7 ± 16% inhibition while U87IDHmut cells were treated with 12 μM XL765 for 24 h, resulting in 61.0 ± 10.6% inhibition (Fig. 1B)

Summary

Introduction

Wild type IDH1 catalyzes the oxidative decarboxylation of isocitrate to α-ketoglutarate (α-KG). In addition to traditional chemotherapies (temozolomide, procarbazine, lomustine and vincristine)[6,31] that affect all dividing cells, therapeutic strategies targeting biologically-relevant growth factors or cell signaling mediators that are altered in cancer are currently being considered[32,33,34] One such cell signaling pathway is the phosphatidylinositol 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) pathway. Inhibitors of the PI3K/mTOR pathway investigated in preclinical studies as well as in clinical trials in GBM and other tumor types, show improved median survival, reduced local and metastatic growth, and tumor growth inhibition[33,44,45,46,47,48]. Based on these earlier findings, inhibitors of the PI3K/mTOR pathway have entered clinical trials for LGG (NCT02023905, NCT01316809)

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