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Cell Metab. 2017 Dec 5;26(6):830-841.e3. doi: 10.1016/j.cmet.2017.10.001. Epub 2017 Oct 19.

In Vivo Imaging of Glutamine Metabolism to the Oncometabolite 2-Hydroxyglutarate in IDH1/2 Mutant Tumors.

Author information

1
Department of Radiology, Memorial Sloan Kettering Cancer Center (MSKCC), New York, NY 10065, USA; Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center (MSKCC), New York, NY 10065, USA.
2
Donald B. and Catherine C. Marron Cancer Metabolism Center, Memorial Sloan Kettering Cancer Center (MSKCC), New York, NY 10065, USA.
3
Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center (MSKCC), New York, NY 10065, USA.
4
Department of Radiology, Memorial Sloan Kettering Cancer Center (MSKCC), New York, NY 10065, USA; Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center (MSKCC), New York, NY 10065, USA; Weill Cornell Medical College, New York, NY 10065, USA. Electronic address: rahimikk@mskcc.org.

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.

KEYWORDS:

2-hydroxyglutarate; glutamine; hyperpolarized imaging; mutant isocitrate dehydrogenase

PMID:
29056515
PMCID:
PMC5718944
[Available on 2018-12-05]
DOI:
10.1016/j.cmet.2017.10.001
[Indexed for MEDLINE]

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