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.
Highlights
Diffuse infiltrative low-grade gliomas (LGGs) are characterized as grade II or III astrocytoma and oligodendroglioma based on histopathological features and genotype including the status of the isocitrate dehydrogenase (IDH) mutation, 1p/19q codeletion and ATRX [1,2,3]
We showed that treatment of cells with the IDH inhibitors AG-120 and AG881 resulted in a partial reversal of the metabolic alterations caused by the mutation [34]
Previous in vitro studies probed the effect of mutant IDH inhibitor AG-881 in prior to investigating patient-derived (BT257 and SF10417) mutant IDH1
Summary
Diffuse infiltrative low-grade gliomas (LGGs) are characterized as grade II or III astrocytoma and oligodendroglioma based on histopathological features and genotype including the status of the isocitrate dehydrogenase (IDH) mutation, 1p/19q codeletion and ATRX [1,2,3]. LGGs typically affect young or middle-aged adults [4]. Diagnosis of LGGs is typically based on symptoms, the most notable of which is seizures, and is confirmed via imaging of non- or mildly contrast enhancing lesions using magnetic resonance imaging patients [7]. One of the challenges in the management of LGGs is their highly infiltrative nature, which limits full surgical resection and leaves behind neoplastic cells within normal-appearing brain tissue [9]. In most cases, tumor recurrence and malignant transformation to a higher grade will occur leading to progressive disabilities and shortened survival [10]
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