Non-invasive methods to image tumor metabolism have outstanding potential and could in principle allow the clinician to predict tumor genetics, stage, likelihood of therapeutic response and other crucial parameters that have direct bearing on patient care. However, the forms of metabolic imaging currently in use - particularly FDG-PET and low-field magnetic resonance spectroscopy - focus on general hallmarks of malignancy and do not provide any specific molecular information about the tumor. Here we propose to develop a method to predict the genotype of gliomas based on in vivo imaging of the """"""""oncometabolite"""""""" 2-hydroxyglutarate (2HG). This metabolite accumulates only in gliomas that bear specific mutations in the genes encoding isocitrate dehydrogenase-1 and -2 (IDH), and the presence of these mutations in gliomas is strongly associated with low- grade lesions and a favorable prognosis. We will develop a proton magnetic resonance spectroscopic imaging (1H-MRSI) technique at 3T for detection of 2HG in the human brain and to determine noninvasively in vivo if the IDH mutations occur in patients with gliomas. Specifically, the research team will investigate spectral editing techniques, including scalar difference editing and multiple-quantum filtering. MRSI sequences will be first designed using computer simulations and will be validated in phantoms and healthy brain in vivo. Next, a clinical study in brain tumor patients will be carried out in patients with low grade gliomas or secondary glioblastomas enrolled in our clinical protocol. Evaluation of the IDH1 status by immunohistochemical (IHC) analysis of resected tumor will be performed and the patients will undergo 1H-MRSI to assess 2-HG status. The results will be correlated with IDH1 mutational status. We will study 30 patients of which we anticipate ~20 will have the mutation. An additional 15 patients with glioblastoma will be studied as negative control subjects since IDH1/2 mutations have not been found in this patient group. This work will lead to the first method to detect a tumor-specific metabolite in vivo. Furthermore, because our approach is easily integrated into existing 3T MR clinical systems and does not require radioactive probes, we anticipate few barriers to its translation into general practice. While this research will facilitate the utility of the proposed technology in the study of gliomas, it should be stressed that the technique will be widely applicable to other diseases in which alterations of 2HG levels are implicated.

Public Health Relevance

The ability to monitor the recently described mutations of cytosolic isocitrate dehydrogenase-1 and -2 noninvasively would be of great utility for making the diagnosis of a low grade glioma, tracking of infiltrative cells during follow up, and for determining response to treatment. We propose to develop a novel proton magnetic resonance spectroscopic imaging tool for measuring the resulting accumulations of the oncometabolite 2-hydroxyglutarate noninvasively in vivo.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Exploratory/Developmental Grants (R21)
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Special Emphasis Panel (ZRG1-DTCS-A (81))
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Zhang, Huiming
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University of Texas Sw Medical Center Dallas
Internal Medicine/Medicine
Schools of Medicine
United States
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Choi, Changho; Raisanen, Jack M; Ganji, Sandeep K et al. (2016) Prospective Longitudinal Analysis of 2-Hydroxyglutarate Magnetic Resonance Spectroscopy Identifies Broad Clinical Utility for the Management of Patients With IDH-Mutant Glioma. J Clin Oncol 34:4030-4039
Ganji, Sandeep K; Maher, Elizabeth A; Choi, Changho (2016) In vivo (1)H MRSI of glycine in brain tumors at 3T. Magn Reson Med 75:52-62
Madan, Akshay; Ganji, Sandeep K; An, Zhongxu et al. (2015) Proton T2 measurement and quantification of lactate in brain tumors by MRS at 3 Tesla in vivo. Magn Reson Med 73:2094-9
Choi, Changho; Ganji, Sandeep K; Madan, Akshay et al. (2014) In vivo detection of citrate in brain tumors by 1H magnetic resonance spectroscopy at 3T. Magn Reson Med 72:316-23
Ganji, Sandeep K; An, Zhongxu; Banerjee, Abhishek et al. (2014) Measurement of regional variation of GABA in the human brain by optimized point-resolved spectroscopy at 7?T in vivo. NMR Biomed 27:1167-75
Choi, Changho; Ganji, Sandeep; Hulsey, Keith et al. (2013) A comparative study of short- and long-TE ¹H MRS at 3 T for in vivo detection of 2-hydroxyglutarate in brain tumors. NMR Biomed 26:1242-50
Choi, Changho; Ganji, Sandeep K; DeBerardinis, Ralph J et al. (2012) 2-hydroxyglutarate detection by magnetic resonance spectroscopy in IDH-mutated patients with gliomas. Nat Med 18:624-9