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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 ?-ketoglutarate (?-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 ?-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] ?-KG flux, could serve as metabolic imaging biomarkers of response to treatment.

SUBMITTER: Molloy AR

PROVIDER: S-EPMC7392019 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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

Molloy Abigail R AR Najac Chloé C Viswanath Pavithra P Lakhani Aliya A Subramani Elavarasan E Batsios Georgios G Radoul Marina M Gillespie Anne Marie AM Pieper Russell O RO Ronen Sabrina M SM

Theranostics 20200709 19

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 ...[more]

PMID: 32754276

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Project description:Alterations in the expression of the Duchenne muscular dystrophy (DMD) gene have been associated with the development, progression and survival outcomes of numerous cancers including tumours of the central nervous system. We undertook a detailed bioinformatic analysis of low-grade glioma (LGG) bulk RNAseq data to characterise the association between DMD expression and LGG survival outcomes. High DMD expression was significantly associated with poor survival in LGG with a difference in median overall survival between high and low DMD groups of over 7 years (P = < 0.0001). In a multivariate model, DMD expression remained significant (P = 0.02) and was an independent prognostic marker for LGG. The effect of DMD expression on overall survival was only apparent in isocitrate dehydrogenase (IDH) mutant cases where non-1p/19q co-deleted LGG patients could be further stratified into high/low DMD groups. Patients in the high DMD group had a median overall survival time almost halve that of the low DMD group. The expression of the individual DMD gene products Dp71, Dp71ab and Dp427m were also significantly associated with overall survival in LGG which have differential biological effects relevant to the pathogenesis of LGG. Differential gene expression and pathway analysis identifies dysregulated biological processes relating to ribosome biogenesis, synaptic signalling, neurodevelopment, morphogenesis and immune pathways. Genes spanning almost the entirety of chromosome 1p are upregulated in patients with high overall DMD, Dp71 and Dp427m expression which worsens survival outcomes for these patients. We confirmed dystrophin protein is variably expressed in LGG tumour tissue by immunohistochemistry and, overall, demonstrate that DMD expression has potential utility as an independent prognostic marker which can further stratify IDH mutant LGG to identify those at risk of poor survival. This knowledge may improve risk stratification and management of LGG.

Dataset Information

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

Publications

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

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