2. Academic Validation
  3. MR-detectable metabolic biomarkers of response to mutant IDH inhibition in low-grade glioma

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

  • Theranostics. 2020 Jul 9;10(19):8757-8770. doi: 10.7150/thno.47317.
Abigail R Molloy 1,  Chloé Najac 1,  Pavithra Viswanath 1,  Aliya Lakhani 1,  Elavarasan Subramani 1,  Georgios Batsios 1,  Marina Radoul 1,  Anne Marie Gillespie 1,  Russell O Pieper 2 3,  Sabrina M Ronen 1 2
Affiliations

Affiliations

  • 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.
PMID: 32754276 DOI: 10.7150/thno.47317
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

AG-120; AG-881; IDH1 mutation; hyperpolarized 13C magnetic resonance spectroscopy; low grade glioma.

Figures
Products