Magnetic Resonance Spectroscopy Studies of Mutant IDH Cells

Sabrina M. Ronen

Several mutations in the gene coding for isocitrate dehydrogenase (IDH) have recently been shown to lead to a neomorphic activity of the expressed mutant enzyme. Rather than catalyzing the conversion of isocitrate to a-ketoglutarate (a-KG), mutant IDH converts a-KG into the oncometabolite 2-hydroxyglutatrate (2-HG).1,2 Importantly, mutations of the cytosolic form of IDH, namely IDH1, are considered one of the first events in the etiology of low-grade glioma. By generating elevated levels of 2-HG, mutant IDH1 leads to inhibition of a-KG-dependent DNA hydroxylases and histone demethylases, resulting in broad epigenetic alterations that ultimately result in glioma development.3

In light of these findings, inhibitors of mutant IDH1 are currently in development, and methods to detect and monitor mutant IDH1 are of interest both for drug development and for patient monitoring. 1H magnetic resonance spectroscopy (MRS) has been shown as a useful non-invasive imaging approach to monitor 2-HG levels both ex vivo and in vivo.4-7 The goal of our work was to develop novel imaging methods that could provide complementary information.

To that end, we have used hyperpolarized 13C MRS and shown that this method can be used to monitor the dynamic production of hyperpolarized 2-HG from α-ketoglutatrate (α-KG) in orthotopic rodent tumors in vivo. We have also shown that additional metabolic reprogramming that is associated with the presence of the IDH1 mutation is detectable by hyperpolarized 13C MRS.

Most notably, we have found that the conversion of hyperpolarized α-KG to glutamate is lower in mutant-IDH1 cells and tumors, an effect that is mediated by the reduced activity of BCAT, GDH, and AST, likely due to the silencing of their expression by mutant IDH1-mediated promoter methylation. The two hyperpolarized 13C MRS-detectable metabolic fluxes, elevated production of 2-HG, and reduced production of glutamate, can thus serve as complementary imaging methods to inform on the presence of the mutation and to enhance our understanding of the biology of mutant IDH1 tumors.8, 9

> INHIBITORS OF MUTANT IDH1 ARE CURRENTLY IN DEVELOPMENT, AND METHODS TO DETECT AND MONITOR MUTANT IDH1 ARE OF INTEREST BOTH FOR DRUG DEVELOPMENT AND FOR PATIENT MONITORING. <

References

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