title: Non-invasive in vivo assessment of IDH1 mutational status in glioma.
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.
authors.affiliation: Department of Radiology and Biomedical Imaging, University of California San Francisco, 1700 4th Street, San Francisco, California 94158, USA.
authors.forename: Myriam M
authors.initials: MM
authors.lastname: Chaumeil
authors.forename: Peder E Z
authors.initials: PE
authors.lastname: Larson
authors.forename: Hikari A I
authors.initials: HA
authors.lastname: Yoshihara
authors.forename: Olivia M
authors.initials: OM
authors.lastname: Danforth
authors.forename: Daniel B
authors.initials: DB
authors.lastname: Vigneron
authors.forename: Sarah J
authors.initials: SJ
authors.lastname: Nelson
authors.forename: Russell O
authors.initials: RO
authors.lastname: Pieper
authors.forename: Joanna J
authors.initials: JJ
authors.lastname: Phillips
authors.forename: Sabrina M
authors.initials: SM
authors.lastname: Ronen
mesh_terms: D000818:Animals; D001932:Brain Neoplasms / Q000201:enzymology* / Q000235:genetics*; D002247:Carbon Isotopes; D002457:Cell Extracts; D045744:Cell Line, Tumor; D004252:DNA Mutational Analysis; D005910:Glioma / Q000201:enzymology* / Q000235:genetics*; D005977:Glutarates / Q000378:metabolism; D006801:Humans; D007521:Isocitrate Dehydrogenase / Q000235:genetics*; D007656:Ketoglutaric Acids / Q000378:metabolism; D009682:Magnetic Resonance Spectroscopy; D050505:Mutant Proteins / Q000378:metabolism; D051381:Rats; D011923:Rats, Nude
chemical_list: D002247:Carbon Isotopes; D002457:Cell Extracts; D005977:Glutarates; D007656:Ketoglutaric Acids; D050505:Mutant Proteins; C019417:alpha-hydroxyglutarate; D007521:Isocitrate Dehydrogenase; C543588:IDH1 protein, human
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