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

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 1 H- and 13 C- 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: 1 H-MRS indicated a significant decrease in steady-state 2-HG following treatment, as expected. This was accompanied by a significant 1 H-MRS-detectable increase in glutamate. However, other metabolites previously linked to 2-HG were not altered. 13 C-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 13 C-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 1 H- and 13 C-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 1 H-MRS-detectable drop in 2-HG, a 1 H-MRS-detectable increase in glutamate, as well as a hyperpolarized 13 C-MRS-detectable change in [1- 13 C] α-KG flux, could serve as metabolic imaging biomarkers of response to treatment.

Early Noninvasive Metabolic Biomarkers of Mutant IDH Inhibition in Glioma

“…It is also in line with reports in both preclinical and clinical studies [26,33,43]. The changes in 2-HG and Glu levels are also in line with our previous observations in the U87IDHmut cells treated with either AG-120 or AG-881 that showed a significant decrease in 2-HG and a significant increase in Glu [34]. GLX, which is also increased in this in vivo study, reflects the sum of Glu and Gln.…”

“…We have shown that cells genetically engineered to express mutant IDH1 increase 2-HG and also decrease Glu, phosphocholine and lactate [37]. However, our previous study in cells [34], as well as the results from this in vivo study, observe a drop in 2-HG and an increase in Glu following mutant IDH inhibition, but no significant changes in lactate or a consistent increase in choline-containing metabolites. Our findings therefore point to the complexity of the molecular biological and metabolic changes that occur in mutant IDH1 tumors during their development and in response to treatment [46].…”

“…2-HG is sometimes present in relatively low levels and its signals overlap with other metabolites, but this challenge has been addressed by development of several advanced data acquisition methods that allow for monitoring of 2-HG both preclinically and clinically [ 23 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 ]. Indeed, 1 H-MRS has been used to monitor the effects of emerging mutant IDH1/2 inhibitors preclinically and in one early clinical study with IDH305 [ 33 , 34 ]. The use of MRS is particularly important because clinical studies to date with three mutant IDH inhibitors, AG-881, IDH305, and AG-120, have all shown that treatment is associated with inhibition of tumor growth and potentially longer patient survival, but no detectable tumor shrinkage has been reported [ 33 , 35 , 36 ].…”

“…Our previous studies in cells have identified the MRS-detectable metabolic alterations characteristic of glioma harboring the IDH1 mutation when compared to wild type IDH1 [ 37 ]. We also showed that treatment of cells with the IDH inhibitors AG-120 and AG-881 resulted in a partial reversal of the metabolic alterations caused by the mutation [ 34 ]. Most notably, we observed that in addition to the expected 1 H-MRS detectable drop in 2-HG, there is a significant increase in glutamate (Glu) following mutant IDH inhibition.…”

Systematic analysis of enhancer regulatory circuit perturbation driven by copy number variations in malignant glioma

“…Glioma is one of the most common brain tumors 1 , 2 , which is classified into grades I-IV according to the World Health Organization (WHO) 3 . Accumulating evidence suggests that perturbation of gene expression is closely associated with carcinogenesis, which might be triggered by genomic rearrangement 4 , site-specific transcription factors 5 , or long-range enhancer interactions 6 .…”