Non-invasive in vivo assessment of IDH1 mutational status in glioma

Nat Commun. 2013:4:2429. doi: 10.1038/ncomms3429.

Abstract

Gain-of-function mutations of the isocitrate dehydrogenase 1 (IDH1) gene are among the most prevalent in low-grade gliomas and secondary glioblastoma. They lead to intracellular accumulation of the oncometabolite 2-hydroxyglutarate, represent an early pathogenic event and are considered a therapeutic target. Here we show, in this proof-of-concept study, that [1-(13)C] α-ketoglutarate can serve as a metabolic imaging agent for non-invasive, real-time, in vivo monitoring of mutant IDH1 activity, and can inform on IDH1 status. Using (13)C magnetic resonance spectroscopy in combination with dissolution dynamic nuclear polarization, the metabolic fate of hyperpolarized [1-(13)C] α-ketoglutarate is studied in isogenic glioblastoma cells that differ only in their IDH1 status. In lysates and tumours that express wild-type IDH1, only hyperpolarized [1-(13)C] α-ketoglutarate can be detected. In contrast, in cells that express mutant IDH1, hyperpolarized [1-(13)C] 2-hydroxyglutarate is also observed, both in cell lysates and in vivo in orthotopic tumours.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Brain Neoplasms / enzymology*
  • Brain Neoplasms / genetics*
  • Carbon Isotopes
  • Cell Extracts
  • Cell Line, Tumor
  • DNA Mutational Analysis
  • Glioma / enzymology*
  • Glioma / genetics*
  • Glutarates / metabolism
  • Humans
  • Isocitrate Dehydrogenase / genetics*
  • Ketoglutaric Acids / metabolism
  • Magnetic Resonance Spectroscopy
  • Mutant Proteins / metabolism
  • Rats
  • Rats, Nude

Substances

  • Carbon Isotopes
  • Cell Extracts
  • Glutarates
  • Ketoglutaric Acids
  • Mutant Proteins
  • alpha-hydroxyglutarate
  • Isocitrate Dehydrogenase
  • IDH1 protein, human