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Theranostics 2020; 10(19):8757-8770. doi:10.7150/thno.47317 This issue Cite

Research Paper

MR-detectable metabolic biomarkers of response to mutant IDH inhibition in low-grade glioma

Abigail R Molloy^1*, Chloé Najac^1*, Pavithra Viswanath¹, Aliya Lakhani¹, Elavarasan Subramani¹, Georgios Batsios¹, Marina Radoul¹, Anne Marie Gillespie¹, Russell O Pieper^2,3, Sabrina M Ronen^1,2✉

1. Department of Radiology and Biomedical Imaging, University of California San Francisco, San Francisco, CA, USA
2. Brain Tumor Center, University of California San Francisco, San Francisco, CA, USA
3. Department of Neurological Surgery, Helen Diller Research Center, University of California San Francisco, San Francisco, CA, USA
*Contributed equally

✉ Corresponding author: Sabrina M. Ronen, 1700 4th Street, Byers Hall 3rd floor Suite, University of California San Francisco, San Francisco, CA 94143. Email: sabrina.ronenedu Phone: +1 415 514 4839

Abstract

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.

Methods: IDH1mut inhibition was confirmed using an enzyme assay and ¹H- and ¹³C- 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: ¹H-MRS indicated a significant decrease in steady-state 2-HG following treatment, as expected. This was accompanied by a significant ¹H-MRS-detectable increase in glutamate. However, other metabolites previously linked to 2-HG were not altered. ¹³C-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 ¹³C-MRS was used to show that the flux of α-KG to both glutamate and 2-HG was modulated by treatment.

Conclusion: In this study, we identified potential ¹H- and ¹³C-MRS-detectable biomarkers of response to IDH1mut inhibition in gliomas. Although further studies are needed to evaluate the utility of these biomarkers in vivo, we expect that in addition to a ¹H-MRS-detectable drop in 2-HG, a ¹H-MRS-detectable increase in glutamate, as well as a hyperpolarized ¹³C-MRS-detectable change in [1-¹³C] α-KG flux, could serve as metabolic imaging biomarkers of response to treatment.

Keywords: IDH1 mutation, low grade glioma, hyperpolarized ¹³C magnetic resonance spectroscopy, AG-881, AG-120

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