In vivo imaging of glutamine metabolism to the oncometabolite 2-hydroxyglutarate in IDH1/2 mutant tumors Journal Article

Authors: Salamanca-Cardona, L.; Shah, H.; Poot, A. J.; Correa, F. M.; Di Gialleonardo, V.; Lui, H.; Miloushev, V. Z.; Granlund, K. L.; Tee, S. S.; Cross, J. R.; Thompson, C. B.; Keshari, K. R.
Article Title: In vivo imaging of glutamine metabolism to the oncometabolite 2-hydroxyglutarate in IDH1/2 mutant tumors
Abstract: The oncometabolite 2-hydroxyglutarate (2-HG) is a signature biomarker in various cancers, where it accumulates as a result of mutations in isocitrate dehydrogenase (IDH). The metabolic source of 2-HG, in a wide variety of cancers, dictates both its generation and also potential therapeutic strategies, but this remains difficult to access in vivo. Here, utilizing patient-derived chondrosarcoma cells harboring endogenous mutations in IDH1 and IDH2, we report that 2-HG can be rapidly generated from glutamine in vitro. Then, using hyperpolarized magnetic resonance imaging (HP-MRI), we demonstrate that in vivo HP [1-13C] glutamine can be used to non-invasively measure glutamine-derived HP 2-HG production. This can be readily modulated utilizing a selective IDH1 inhibitor, opening the door to targeting glutamine-derived 2-HG therapeutically. Rapid rates of HP 2-HG generation in vivo further demonstrate that, in a context-dependent manner, glutamine can be a primary carbon source for 2-HG production in mutant IDH tumors. Salamanca-Cardona et al. show that glutamine is a primary carbon source for the biosynthesis of the oncometabolite 2-hydroxyglutarate in mutant IDH tumors. They develop a novel hyperpolarized MRI method using glutamine as a probe to detect 2-hydroxyglutarate formation in vivo in real time, non-invasively, and with high specificity. © 2017 Elsevier Inc.
Keywords: controlled study; treatment response; gene mutation; human cell; nonhuman; neuroimaging; nuclear magnetic resonance imaging; positron emission tomography; mouse; animal experiment; animal model; ph; in vivo study; in vitro study; biosynthesis; glioma cell; glutamine; polarization; cell mutant; proton nuclear magnetic resonance; carbon nuclear magnetic resonance; tumor microenvironment; citric acid cycle; 2 hydroxyglutaric acid; isocitrate dehydrogenase 1; liquid chromatography-mass spectrometry; amino acid metabolism; magnetic field; carbon source; 2-hydroxyglutarate; isocitrate dehydrogenase 2; hyperpolarization; pyroglutamic acid; human; female; priority journal; article; metabolic rate; hyperpolarized imaging; mutant isocitrate dehydrogenase; jj012 cell line
Journal Title: Cell Metabolism
Volume: 26
Issue: 6
ISSN: 1550-4131
Publisher: Elsevier Inc.  
Date Published: 2017-12-05
Start Page: 830
End Page: 841.e3
Language: English
DOI: 10.1016/j.cmet.2017.10.001
PROVIDER: scopus
PMCID: PMC5718944
PUBMED: 29056515
Notes: Article -- Export Date: 2 January 2018 -- Source: Scopus
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