MR-detectable Metabolic Biomarkers of Response to Mutant IDH Inhibition in Low-grade Glioma

Mutations in isocitrate dehydrogenase 1 (IDH1mut) are reported in 70-90% of low-grade gliomas and secondary glioblastomas. IDH1mut catalyzes the reduction of α-ketoglutarate (α-KG) to 2-hydroxyglutarate (2-HG), an oncometabolite which drives tumorigenesis. Inhibition of IDH1mut is therefore an emerging therapeutic approach, and inhibitors such as AG-120 and AG-881 have shown promising results in phase 1 and 2 clinical studies. However, detection of response to these therapies prior to changes in tumor growth can be challenging. The goal of this study was to identify non-invasive clinically translatable metabolic imaging biomarkers of IDH1mut inhibition that can serve to assess response. IDH1mut inhibition was confirmed using an enzyme assay and H- and C- magnetic resonance spectroscopy (MRS) were used to investigate the metabolic effects of AG-120 and AG-881 on two genetically engineered IDH1mut-expressing cell lines, NHAIDH1mut and U87IDH1mut. H-MRS indicated a significant decrease in steady-state 2-HG following treatment, as expected. This was accompanied by a significant H-MRS-detectable increase in glutamate. However, other metabolites previously linked to 2-HG were not altered. C-MRS also showed that the steady-state changes in glutamate were associated with a modulation in the flux of glutamine to both glutamate and 2-HG. Finally, hyperpolarized C-MRS was used to show that the flux of α-KG to both glutamate and 2-HG was modulated by treatment. In this study, we identified potential H- and C-MRS-detectable biomarkers of response to IDH1mut inhibition in gliomas. Although further studies are needed to evaluate the utility of these biomarkers , we expect that in addition to a H-MRS-detectable drop in 2-HG, a H-MRS-detectable increase in glutamate, as well as a hyperpolarized C-MRS-detectable change in [1-C] α-KG flux, could serve as metabolic imaging biomarkers of response to treatment.