2. Academic Validation
  3. Early Noninvasive Metabolic Biomarkers of Mutant IDH Inhibition in Glioma

Early Noninvasive Metabolic Biomarkers of Mutant IDH Inhibition in Glioma

  • Metabolites. 2021 Feb 13;11(2):109. doi: 10.3390/metabo11020109.
Marina Radoul 1,  Donghyun Hong 1,  Anne Marie Gillespie 1,  Chloé Najac 1,  Pavithra Viswanath 1,  Russell O Pieper 2 3,  Joseph F Costello 2,  Hema Artee Luchman 4,  Sabrina M Ronen 1 3
Affiliations

Affiliations

  • 1 Department of Radiology and Biomedical Imaging, University of California, San Francisco, CA 94158, USA.
  • 2 Department of Neurological Surgery, Helen Diller Research Center, University of California, San Francisco, CA 94158, USA.
  • 3 Brain Tumor Research Center, University of California, San Francisco, CA 94158, USA.
  • 4 Arnie Charbonneau Cancer Institute and Hotchkiss Brain Institute, University of Calgary, Calgary, AB T2N 4N1, Canada.
PMID: 33668509 DOI: 10.3390/metabo11020109
Abstract

Approximately 80% of low-grade glioma (LGGs) harbor mutant isocitrate dehydrogenase 1/2 (IDH1/2) driver mutations leading to accumulation of the oncometabolite 2-hydroxyglutarate (2-HG). Thus, inhibition of mutant IDH is considered a potential therapeutic target. Several mutant IDH inhibitors are currently in clinical trials, including AG-881 and BAY-1436032. However, to date, early detection of response remains a challenge. In this study we used high resolution 1H magnetic resonance spectroscopy (1H-MRS) to identify early noninvasive MR (Magnetic Resonance)-detectable metabolic biomarkers of response to mutant IDH inhibition. In vivo 1H-MRS was performed on mice orthotopically-implanted with either genetically engineered (U87IDHmut) or patient-derived (BT257 and SF10417) mutant IDH1 cells. Treatment with either AG-881 or BAY-1436032 induced a significant reduction in 2-HG. Moreover, both inhibitors led to a significant early and sustained increase in glutamate and the sum of glutamate and glutamine (GLX) in all three models. A transient early increase in N-acetylaspartate (NAA) was also observed. Importantly, all models demonstrated enhanced animal survival following both treatments and the metabolic alterations were observed prior to any detectable differences in tumor volume between control and treated tumors. Our study therefore identifies potential translatable early metabolic biomarkers of drug delivery, mutant IDH inhibition and glioma response to treatment with emerging clinically relevant therapies.

Keywords

1H-MRS; glioma; mutant IDH inhibitor; noninvasive metabolic biomarkers.

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