title: Hyperpolarized (13)C MR imaging detects no lactate production in mutant IDH1 gliomas: Implications for diagnosis and response monitoring.
abstract: Metabolic imaging of brain tumors using (13)C Magnetic Resonance Spectroscopy (MRS) of hyperpolarized [1-(13)C] pyruvate is a promising neuroimaging strategy which, after a decade of preclinical success in glioblastoma (GBM) models, is now entering clinical trials in multiple centers. Typically, the presence of GBM has been associated with elevated hyperpolarized [1-(13)C] lactate produced from [1-(13)C] pyruvate, and response to therapy has been associated with a drop in hyperpolarized [1-(13)C] lactate. However, to date, lower grade gliomas had not been investigated using this approach. The most prevalent mutation in lower grade gliomas is the isocitrate dehydrogenase 1 (IDH1) mutation, which, in addition to initiating tumor development, also induces metabolic reprogramming. In particular, mutant IDH1 gliomas are associated with low levels of lactate dehydrogenase A (LDHA) and monocarboxylate transporters 1 and 4 (MCT1, MCT4), three proteins involved in pyruvate metabolism to lactate. We therefore investigated the potential of (13)C MRS of hyperpolarized [1-(13)C] pyruvate for detection of mutant IDH1 gliomas and for monitoring of their therapeutic response. We studied patient-derived mutant IDH1 glioma cells that underexpress LDHA, MCT1 and MCT4, and wild-type IDH1 GBM cells that express high levels of these proteins. Mutant IDH1 cells and tumors produced significantly less hyperpolarized [1-(13)C] lactate compared to GBM, consistent with their metabolic reprogramming. Furthermore, hyperpolarized [1-(13)C] lactate production was not affected by chemotherapeutic treatment with temozolomide (TMZ) in mutant IDH1 tumors, in contrast to previous reports in GBM. Our results demonstrate the unusual metabolic imaging profile of mutant IDH1 gliomas, which, when combined with other clinically available imaging methods, could be used to detect the presence of the IDH1 mutation in vivo.
authors.affiliation: Department of Radiology and Biomedical Imaging, Mission Bay Campus, 1700 4th Street, Byers Hall, University of California, 94158 San Francisco, CA, United States.
authors.forename: Myriam M
authors.initials: MM
authors.lastname: Chaumeil
authors.affiliation: Department of Radiology and Biomedical Imaging, Mission Bay Campus, 1700 4th Street, Byers Hall, University of California, 94158 San Francisco, CA, United States.
authors.forename: Marina
authors.initials: M
authors.lastname: Radoul
authors.affiliation: Department of Radiology and Biomedical Imaging, Mission Bay Campus, 1700 4th Street, Byers Hall, University of California, 94158 San Francisco, CA, United States.
authors.forename: Chloé
authors.initials: C
authors.lastname: Najac
authors.affiliation: Department of Radiology and Biomedical Imaging, Mission Bay Campus, 1700 4th Street, Byers Hall, University of California, 94158 San Francisco, CA, United States.
authors.forename: Pia
authors.initials: P
authors.lastname: Eriksson
authors.affiliation: Department of Radiology and Biomedical Imaging, Mission Bay Campus, 1700 4th Street, Byers Hall, University of California, 94158 San Francisco, CA, United States.
authors.forename: Pavithra
authors.initials: P
authors.lastname: Viswanath
authors.affiliation: Department of Clinical Neurosciences, Foothills Hospital, 1403 29 St NW, Calgary, AB T2N 2T9, Canada.
authors.forename: Michael D
authors.initials: MD
authors.lastname: Blough
authors.affiliation: Department of Clinical Neurosciences, Foothills Hospital, 1403 29 St NW, Calgary, AB T2N 2T9, Canada.
authors.forename: Charles
authors.initials: C
authors.lastname: Chesnelong
authors.affiliation: Department of Clinical Neurosciences, Foothills Hospital, 1403 29 St NW, Calgary, AB T2N 2T9, Canada.
authors.forename: H Artee
authors.initials: HA
authors.lastname: Luchman
authors.affiliation: Department of Clinical Neurosciences, Foothills Hospital, 1403 29 St NW, Calgary, AB T2N 2T9, Canada.
authors.forename: J Gregory
authors.initials: JG
authors.lastname: Cairncross
authors.affiliation: Department of Radiology and Biomedical Imaging, Mission Bay Campus, 1700 4th Street, Byers Hall, University of California, 94158 San Francisco, CA, United States; Brain Tumor Research Center, Helen Diller Family Cancer Research Building, 1450 3rd Street, University of California, 94158 San Francisco, CA, United States.
authors.forename: Sabrina M
authors.initials: SM
authors.lastname: Ronen
mesh_terms: D014408:Biomarkers, Tumor / Q000378:metabolism*; D001932:Brain Neoplasms / Q000000981:diagnostic imaging* / Q000235:genetics / Q000378:metabolism; D066241:Carbon-13 Magnetic Resonance Spectroscopy / Q000379:methods*; D005910:Glioma / Q000000981:diagnostic imaging* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007521:Isocitrate Dehydrogenase / Q000378:metabolism*; D019344:Lactic Acid / Q000378:metabolism*; D019289:Pyruvic Acid / Q000378:metabolism*; D014407:Tumor Cells, Cultured
chemical_list: D014408:Biomarkers, Tumor; D019344:Lactic Acid; D019289:Pyruvic Acid; D007521:Isocitrate Dehydrogenase; C543588:IDH1 protein, human
keywords: 2-HG, 2-hydroxyglutarate; AIF, arterial input function; AUC, area under the curve; DNP, dynamic nuclear polarization; DNP-MR, dynamic nuclear polarization magnetic resonance; EGF, epidermal growth factor; EGFR, epidermal growth factor receptor; FA, flip angle; FGF, fibroblast growth factor; FLAIR, fluid attenuated inversion recovery; FOV, field of view; GBM, glioblastoma; Glioma; Hyperpolarized 13C Magnetic Resonance Spectroscopy (MRS); IDH1, isocitrate dehydrogenase 1; Isocitrate dehydrogenase 1 (IDH1) mutation; LDHA, lactate dehydrogenase A; MCT1, monocarboxylate transporter 1; MCT4, monocarboxylate transporter 4; MR, magnetic resonance; MRI, magnetic resonance imaging; MRS, magnetic resonance spectroscopic imaging; MRS, magnetic resonance spectroscopy; Metabolic reprogramming; NA, number of averages; NT, number of transients; PBS, phosphate-buffer saline; PDGF, platelet-derived growth factor; PET, positron emission tomography; PI3K, phosphoinositide 3-kinase; PTEN, phosphatase and tensin homolog; RB1, retinoblastoma protein 1; SLC16A1, solute carrier family 16 member 1; SLC16A3, solute carrier family 16 member 3; SNR, signal-to-noise ratio; SW, spectral width; TCGA, The Cancer Genome Atlas; TE, echo time; TMZ, temozolomide; TP53, tumor protein p53; TR, repetition time; Tacq, acquisition time; VOI, voxel of interest; mTOR, mammalian target of rapamycin; α-KG, α-ketoglutarate