title: Hyperpolarized [1-13C] glutamate: a metabolic imaging biomarker of IDH1 mutational status in glioma.
abstract: Mutations of the isocitrate dehydrogenase 1 (IDH1) gene are among the most prevalent in low-grade glioma and secondary glioblastoma, represent an early pathogenic event, and are associated with epigenetically driven modulations of metabolism. Of particular interest is the recently uncovered relationship between the IDH1 mutation and decreased activity of the branched-chain amino acid transaminase 1 (BCAT1) enzyme. Noninvasive imaging methods that can assess BCAT1 activity could therefore improve detection of mutant IDH1 tumors and aid in developing and monitoring new targeted therapies. BCAT1 catalyzes the transamination of branched-chain amino acids while converting α-ketoglutarate (α-KG) to glutamate. Our goal was to use (13)C magnetic resonance spectroscopy to probe the conversion of hyperpolarized [1-(13)C] α-KG to hyperpolarized [1-(13)C] glutamate as a readout of BCAT1 activity. We investigated two isogenic glioblastoma lines that differed only in their IDH1 status and performed experiments in live cells and in vivo in rat orthotopic tumors. Following injection of hyperpolarized [1-(13)C] α-KG, hyperpolarized [1-(13)C] glutamate production was detected both in cells and in vivo, and the level of hyperpolarized [1-(13)C] glutamate was significantly lower in mutant IDH1 cells and tumors compared with their IDH1-wild-type counterparts. Importantly however, in our cells the observed drop in hyperpolarized [1-(13)C] glutamate was likely mediated not only by a drop in BCAT1 activity, but also by reductions in aspartate transaminase and glutamate dehydrogenase activities, suggesting additional metabolic reprogramming at least in our model. Hyperpolarized [1-(13)C] glutamate could thus inform on multiple mutant IDH1-associated metabolic events that mediate reduced glutamate production.
authors.affiliation: Departments of Radiology and Biomedical Imaging.
authors.forename: Myriam M
authors.initials: MM
authors.lastname: Chaumeil
authors.affiliation: Departments of Radiology and Biomedical Imaging.
authors.forename: Peder E Z
authors.initials: PE
authors.lastname: Larson
authors.affiliation: Departments of Radiology and Biomedical Imaging.
authors.forename: Sarah M
authors.initials: SM
authors.lastname: Woods
authors.affiliation: Departments of Radiology and Biomedical Imaging.
authors.forename: Larry
authors.initials: L
authors.lastname: Cai
authors.affiliation: Departments of Radiology and Biomedical Imaging.
authors.forename: Pia
authors.initials: P
authors.lastname: Eriksson
authors.affiliation: Pathology, and Neurological Surgery, Helen Diller Research Center; and Brain Tumor Research Center, University of California San Francisco, San Francisco, California.
authors.forename: Aaron E
authors.initials: AE
authors.lastname: Robinson
authors.affiliation: Departments of Radiology and Biomedical Imaging.
authors.forename: Janine M
authors.initials: JM
authors.lastname: Lupo
authors.affiliation: Departments of Radiology and Biomedical Imaging.
authors.forename: Daniel B
authors.initials: DB
authors.lastname: Vigneron
authors.affiliation: Departments of Radiology and Biomedical Imaging.
authors.forename: Sarah J
authors.initials: SJ
authors.lastname: Nelson
authors.affiliation: Neurological Surgery, Helen Diller Research Center; and Brain Tumor Research Center, University of California San Francisco, San Francisco, California.
authors.forename: Russell O
authors.initials: RO
authors.lastname: Pieper
authors.affiliation: Pathology, and Neurological Surgery, Helen Diller Research Center; and Brain Tumor Research Center, University of California San Francisco, San Francisco, California.
authors.forename: Joanna J
authors.initials: JJ
authors.lastname: Phillips
authors.affiliation: Departments of Radiology and Biomedical Imaging, Brain Tumor Research Center, University of California San Francisco, San Francisco, California sabrina.ronen@ucsf.edu.
authors.forename: Sabrina M
authors.initials: SM
authors.lastname: Ronen
mesh_terms: D000818:Animals; D014408:Biomarkers, Tumor; D001932:Brain Neoplasms / Q000201:enzymology / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D066241:Carbon-13 Magnetic Resonance Spectroscopy / Q000379:methods; D045744:Cell Line, Tumor; D005910:Glioma / Q000201:enzymology / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D018698:Glutamic Acid / Q000032:analysis / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D007521:Isocitrate Dehydrogenase / Q000235:genetics* / Q000378:metabolism; D007656:Ketoglutaric Acids / Q000378:metabolism; D008297:Male; D009154:Mutation; D019275:Radiopharmaceuticals / Q000032:analysis / Q000737:chemistry / Q000378:metabolism; D051381:Rats; D011923:Rats, Nude; D000637:Transaminases / Q000378:metabolism
chemical_list: D014408:Biomarkers, Tumor; D007656:Ketoglutaric Acids; D019275:Radiopharmaceuticals; D018698:Glutamic Acid; D007521:Isocitrate Dehydrogenase; C490590:BCAT1 protein, human; C490589:Bcat1 protein, rat; D000637:Transaminases