MR-detectable metabolic biomarkers of response to mutant IDH inhibition in low-grade glioma
Abigail R. Molloy, Chloé Najac, Pavithra Viswanath, Aliya Lakhani, Elavarasan Subramani, Georgios Batsios, Marina Radoul, Anne Marie Gillespie, Russell O. Pieper, Sabrina M. Ronen
Abstract
Mutations in isocitrate dehydrogenase 1 (IDH1mut) are reported in 70-90% of low-grade gliomas and secondary glioblastomas. IDH1mut catalyzes the reduction of -ketoglutarate (-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. Methods: IDH1mut inhibition was confirmed using an enzyme assay and 1 H-and 13 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. Results: 1 H-MRS indicated a significant decrease in steady-state 2-HG following treatment, as expected. This was accompanied by a significant 1 H-MRS-detectable increase in glutamate. However, other metabolites previously linked to 2-HG were not altered. 13 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 13 C-MRS was used to show that the flux of -KG to both glutamate and 2-HG was modulated by treatment.