Ward, P. S. et al. The common feature of leukemia-associated IDH1 and IDH2 mutations is a neomorphic enzyme activity converting alpha-ketoglutarate to 2-hydroxyglutarate. Cancer Cell 17, 225–234 (2010).
Dang, L. et al. Cancer-associated IDH1 mutations produce 2-hydroxyglutarate. Nature 462, 739–744 (2009).
Mardis, E. R. et al. Recurring mutations found by sequencing an acute myeloid leukemia genome. N. Engl. J. Med. 361, 1058–1066 (2009).
Ohgaki, H. & Kleihues, P. The definition of primary and secondary glioblastoma. Clin. Cancer Res. 19, 764–772 (2013).
Yang, H., Ye, D., Guan, K. L. & Xiong, Y. IDH1 and IDH2 mutations in tumorigenesis: mechanistic insights and clinical perspectives. Clin. Cancer Res. 18, 5562–5571 (2012).
Losman, J. A. & Kaelin, W. G. Jr. What a difference a hydroxyl makes: mutant IDH, (R)-2-hydroxyglutarate, and cancer. Genes Dev. 27, 836–852 (2013).
Walker, E. J. et al. Monoallelic expression determines oncogenic progression and outcome in benign and malignant brain tumors. Cancer Res. 72, 636–644 (2012).
Leonardi, R., Subramanian, C., Jackowski, S. & Rock, C. O. Cancer-associated isocitrate dehydrogenase mutations inactivate NADPH-dependent reductive carboxylation. J. Biol. Chem. 287, 14615–14620 (2012).
Ward, P. S. et al. The potential for isocitrate dehydrogenase mutations to produce 2-hydroxyglutarate depends on allele specificity and subcellular compartmentalization. J. Biol. Chem. 288, 3804–3815 (2013).
Turcan, S. et al. IDH1 mutation is sufficient to establish the glioma hypermethylator phenotype. Nature 483, 479–483 (2012).
Xu, W. et al. Oncometabolite 2-hydroxyglutarate is a competitive inhibitor of alpha-ketoglutarate-dependent dioxygenases. Cancer Cell 19, 17–30 (2011).
Huse, J. T., Phillips, H. S. & Brennan, C. W. Molecular subclassification of diffuse gliomas: seeing order in the chaos. Glia 59, 1190–1199 (2011).
Lu, C. et al. IDH mutation impairs histone demethylation and results in a block to cell differentiation. Nature 483, 474–478 (2012).
Popovici-Muller, J. et al. Discovery of the first potent inhibitors of mutant IDH1 that lower tumor 2-HG in vivo. Acs Med. Chem. Lett. 3, 850–855 (2012).
Rohle, D. et al. An inhibitor of mutant IDH1 delays growth and promotes differentiation of glioma cells. Science 340, 626–630 (2013).
Nelson, S. J. Assessment of therapeutic response and treatment planning for brain tumors using metabolic and physiological MRI. NMR Biomed. 24, 734–749 (2011).
Julia-Sape, M. et al. Prospective diagnostic performance evaluation of single-voxel 1H MRS for typing and grading of brain tumours. NMR Biomed. 25, 661–673 (2012).
Andronesi, O. C. et al. Detection of 2-hydroxyglutarate in IDH-mutated glioma patients by in vivo spectral-editing and 2D correlation magnetic resonance spectroscopy. Sci. Transl. Med. 4, 116ra114 (2012).
Choi, C. et al. 2-hydroxyglutarate detection by magnetic resonance spectroscopy in IDH-mutated patients with gliomas. Nat. Med. 18, 624–629 (2012).
Pope, W. B. et al. Non-invasive detection of 2-hydroxyglutarate and other metabolites in IDH1 mutant glioma patients using magnetic resonance spectroscopy. J. Neurooncol. 107, 197–205 (2012).
Esmaeili, M., Vettukattil, R. & Bathen, T. F. 2-hydroxyglutarate as a magnetic resonance biomarker for glioma subtyping. Transl. Oncol. 6, 92–98 (2013).
Lazovic, J. et al. Detection of 2-hydroxyglutaric acid in vivo by proton magnetic resonance spectroscopy in U87 glioma cells overexpressing isocitrate dehydrogenase-1 mutation. Neuro. Oncol. 14, 1465–1472 (2012).
Chaumeil, M. M. et al. In vivo comparison of total and hyperpolarized lactate levels assessed by localized 1H MRS and hyperpolarized 13C MRSI in glioblastoma models at 14.1Tesla. inInternational Society of Magnetic Resonance in Medicine Vol. 4375, Melbourne (2012).
Kalinina, J. et al. Detection of ‘oncometabolite’ 2-hydroxyglutarate by magnetic resonance analysis as a biomarker of IDH1/2 mutations in glioma. J. Mol. Med. 90, 1161–1171 (2012).
Elkhaled, A. et al. Magnetic resonance of 2-hydroxyglutarate in IDH1-mutated low-grade gliomas. Sci. Transl. Med. 4, 116ra115 (2012).
Ardenkjaer-Larsen, J. H. et al. Increase in signal-to-noise ratio of >10,000 times in liquid-state NMR. Proc. Natl Acad. Sci. USA 100, 10158–10163 (2003).
Kurhanewicz, J. et al. Analysis of cancer metabolism by imaging hyperpolarized nuclei: prospects for translation to clinical research. Neoplasia 13, 81–97 (2011).
Day, S. E. et al. Detecting tumor response to treatment using hyperpolarized 13C magnetic resonance imaging and spectroscopy. Nat. Med. 13, 1382–1387 (2007).
Ward, C. S. et al. Noninvasive detection of target modulation following phosphatidylinositol 3-kinase inhibition using hyperpolarized 13C magnetic resonance spectroscopy. Cancer Res. 70, 1296–1305 (2010).
Park, I. et al. Detection of early response to temozolomide treatment in brain tumors using hyperpolarized 13C MR metabolic imaging. J. Magn. Reson. Imaging 33, 1284–1290 (2011).
Chaumeil, M. M. et al. Hyperpolarized 13C MR spectroscopic imaging can be used to monitor Everolimus treatment in vivo in an orthotopic rodent model of glioblastoma. Neuroimage 59, 193–201 (2012).
Day, S. E. et al. Detecting response of rat C6 glioma tumors to radiotherapy using hyperpolarized [1- 13C]pyruvate and 13C magnetic resonance spectroscopic imaging. Magn. Reson. Med. 65, 557–563 (2011).
Nelson, S. J. et al. Metabolic imaging of patients with prostate cancer using hyperpolarized [1-13C]pyruvate. Sci. Transl. Med. 5, 198ra108 (2013).
Larson, P. E. et al. Multiband excitation pulses for hyperpolarized 13C dynamic chemical-shift imaging. J. Magn. Reson. 194, 121–127 (2008).
Xing, Y., Reed, G. D., Pauly, J. M., Kerr, A. B. & Larson, P. E. Z. Optimal variable flip angle schemes for multi-band dynamic acquisition of hyperpolarized 13C MRSI. J. Magn. Reson. 234, 75–81 (2013).
Cunningham, C. H. et al. Double spin-echo sequence for rapid spectroscopic imaging of hyperpolarized 13C. J. Magn. Reson. 187, 357–362 (2007).
Larson, P. E. et al. Investigation of tumor hyperpolarized [1-13C]-pyruvate dynamics using time-resolved multiband RF excitation echo-planar MRSI. Magn. Reson. Med. 63, 582–591 (2010).
Kazan, S. M. et al. Kinetic modeling of hyperpolarized (13) C pyruvate metabolism in tumors using a measured arterial input function. Magn. Reson. Med (e-pub ahead of print 20 November 2012; doi:10.1002/mrm.24546).
Chen, A. P. et al. Hyperpolarized C-13 spectroscopic imaging of the TRAMP mouse at 3T-initial experience. Magn. Reson. Med. 58, 1099–1106 (2007).
Chen, A. P. et al. Feasibility of using hyperpolarized [1-13C]lactate as a substrate for in vivo metabolic 13C MRSI studies. Magn. Reson. Imaging 26, 721–726 (2008).
Hu, S. et al. In vivo measurement of normal rat intracellular pyruvate and lactate levels after injection of hyperpolarized [1-(13)C]alanine. Magn. Reson. Imaging 29, 1035–1040 (2011).
Ardenkjaer-Larsen, J. H. et al. Dynamic nuclear polarization polarizer for sterile use intent. NMR Biomed. 24, 927–932 (2011).
Batel, M. et al. A multi-sample 94 GHz dissolution dynamic-nuclear-polarization system. J. Magn. Reson. 214, 166–174 (2012).
Luchman, H. A. et al. An in vivo patient-derived model of endogenous IDH1-mutant glioma. Neuro. Oncol. 14, 184–191 (2012).
MacKenzie, E. D. et al. Cell-permeating alpha-ketoglutarate derivatives alleviate pseudohypoxia in succinate dehydrogenase-deficient cells. Mol. Cell Biol. 27, 3282–3289 (2007).
Shank, R. P. & Bennett, D. J. 2-Oxoglutarate transport: a potential mechanism for regulating glutamate and tricarboxylic acid cycle intermediates in neurons. Neurochem. Res. 18, 401–410 (1993).
Smolkova, K. & Jezek, P. The role of mitochondrial NADPH-dependent isocitrate dehydrogenase in cancer cells. Int. J. Cell Biol. 2012, 273947 (2012).
Hurd, R. E. et al. Metabolic imaging in the anesthetized rat brain using hyperpolarized [1-13C] pyruvate and [1-13C] ethyl pyruvate. Magn. Reson. Med. 63, 1137–1143 (2010).
Park, I. et al. Hyperpolarized 13C magnetic resonance metabolic imaging: application to brain tumors. Neuro. Oncol. 12, 133–144 (2010).
Bhattacharya, R., Gujar, N., Singh, P., Rao, P. & Vijayaraghavan, R. Toxicity of alpha-ketoglutarate following 14-days repeated oral administration in Wistar rats. Cell. Mol. Biol. 57, SupplOL1543–OL1549 (2011).
Marjanska, M. et al. In vivo13C spectroscopy in the rat brain using hyperpolarized [1-(13)C]pyruvate and [2-(13)C]pyruvate. J. Magn. Reson. 206, 210–218 (2010).
Gallagher, F. A. et al. Production of hyperpolarized [1,4-13C2]malate from [1,4-13C2]fumarate is a marker of cell necrosis and treatment response in tumors. Proc. Natl Acad. Sci. USA 106, 19801–19806 (2009).
Golman, K., Zandt, R. I., Lerche, M., Pehrson, R. & Ardenkjaer-Larsen, J. H. Metabolic imaging by hyperpolarized 13C magnetic resonance imaging for in vivo tumor diagnosis. Cancer Res. 66, 10855–10860 (2006).
Fatania, H. R., al-Nassar, K. E. & Thomas, N. Chemical modification of rat liver cytosolic NADP(+)-linked isocitrate dehydrogenase by N-ethylmaleimide. Evidence for essential sulphydryl groups. FEBS Lett. 322, 245–248 (1993).
Yan, H. et al. IDH1 and IDH2 mutations in gliomas. N. Engl. J. Med. 360, 765–773 (2009).
Ozawa, T. et al. Growth of human glioblastomas as xenografts in the brains of athymic rats. In Vivo 16, 55–60 (2002).
Brandes, A. H., Ward, C. S. & Ronen, S. M. 17-allyamino-17-demethoxygeldanamycin treatment results in a magnetic resonance spectroscopy-detectable elevation in choline-containing metabolites associated with increased expression of choline transporter SLC44A1 and phospholipase A2. Breast Cancer Res. 12, R84 (2010).
Ohliger, M. A. et al. Combined parallel and partial fourier MR reconstruction for accelerated 8-channel hyperpolarized carbon-13 in vivo magnetic resonance spectroscopic imaging (MRSI). J. Magn. Reson. Imaging (e-pub ahead of print 4 January 2013; doi:10.1002/Jmri.23989).