CBMT-10. MUTANT ISOCITRATE DEHYDROGENASE 1 INHIBITION INDUCES A UNIQUE MRS-DETECTABLE METABOLIC SIGNATURE IN LOW-GRADE GLIOMAS

• Published in: Neuro-oncology (Charlottesville, Va.) Vol. 21; no. Supplement_6; pp. vi34 - vi35
• Main Authors: Molloy, Abigail, Lakhani, Aliya, Najac, Chloé, Subramani, Elavarasan, Marie Gillespie, Anne, Pieper, Russell O, Viswanath, Pavithra, Ronen, Sabrina
• Format: Journal Article
• Language: English
• Published: US Oxford University Press 11.11.2019
• Subjects: Cell Biology and Metabolism
• ISSN: 1522-8517; 1523-5866
• DOI: 10.1093/neuonc/noz175.132

Abstract Mutations in isocitrate dehydrogenase 1/2 (IDHmut) are reported in 70–90% of low-grade gliomas and secondary glioblastomas. IDHmut catalyzes the reduction of a-ketoglutarate (a-KG) to 2-hydroxyglutarate (2-HG), an oncometabolite that drives tumorigenesis. Inhibition of IDHmut is therefore a rapidly emerging therapeutic approach and IDHmut inhibitors such as AG-120 and AG-881 have shown promising results in phase 1 and 2 clinical studies. The goal of this study was to identify early non-invasive metabolic biomarkers of IDHmut inhibition that can serve to moniter response to these therapies. We used 1H and 13C magnetic resonance spectroscopy (MRS) to investigate the response of two genetically-engineered IDHmut cell lines (U87-based and normal human astrocyte-based) to AG-120 and AG-881 treatment. As expected, in both cell lines, our 1H-MRS data indicated that AG-120 and AG-881 induced a significant decrease in 2-HG. Interestingly however, we also observed a significant increase in phosphocholine and glutamate, pointing to broader changes in the metabolism of treated cells and a unique MRS signature. To further investigate the increase in glutamate induced by AG-120 and AG-881 in our models, we used 13C-MRS and quantified the flux of [1-13C] glucose and [3-13C] glutamine to 13C-labeled glutamate. Our results indicate that both AG-120 and AG-881 significantly increase the flux of 13C-labeled glutamine to 13C glutamate, while the flux of 13C-labeled glucose to 13C glutamate remained unchanged. Further studies are currently underway to explore the utility of using hyperpolarized [1-13C]-glutamine and hyperpolarized [1-13C]-a-KG for monitoring flux to glutamate and 2-HG, and to validate these probes as additional biomarkers of response to IDHmut inhibition. Taken together, our studies indicate that IDHmut inhibition induces a unique MRS-detectable metabolic profile that can potentially be exploited for early non-invasive, clinically translatable detection of response to emerging IDHmut inhibitors.