Altered cancer cell metabolism in gliomas with mutant IDH1 or IDH2.

PURPOSE OF REVIEW

IDH1/2 mutations occur in up to 70% of low-grade gliomas and secondary glioblastomas. Mutation of these enzymes reduces the wildtype function of the enzyme (conversion of isocitrate to α-ketoglutarate) while conferring a new enzymatic function, the production of D-2-hydroxyglutarate (D-2-HG) from α-ketoglutarate (α-KG). However, it is unclear how these enzymatic changes contribute to tumorigenesis. Here, we discuss the recent studies that demonstrate how IDH1/2 mutation may alter the metabolism and epigenome of gliomas, how these changes may contribute to tumor formation, and opportunities they might provide for molecular targeting.

RECENT FINDINGS

Metabolomic studies of IDH1/2 mutant cells have revealed alterations in glutamine, fatty acid, and citrate synthesis pathways. Additionally, D-2-HG produced by IDH1/2 mutant cells can competitively inhibit α-KG-dependent enzymes, including histone demethylases and DNA hydroxylases, potentially leading to a distinct epigenetic phenotype. Alterations in metabolism and DNA methylation present possible mechanisms of tumorigenesis.

SUMMARY

Recent attempts to improve outcomes for glioma patients have resulted in incremental gains. Studies of IDH1/2 mutations have provided mechanistic insights into tumorigenesis and potential avenues for therapeutic intervention. Further study of IDH1/2 mutations might allow for improved therapeutic strategies.