Low grade gliomas (LGG) represent a third of all gliomas in adults. They occur in young patients, with a median age of 30, and have a greater than 80% risk of transformation to glioblastoma (GBM) over a 5-10 year period. There are currently no effective treatments for LGG and no chemotherapy that can prevent the transformation to GBM. Recently mutations have been identified in two isoforms of isocitrate dehydrogenase (IDH1 in the cytosol or IDH2 in the mitochondria) in >70% of LGGs. Clinically, the presence of an IDH mutation has been shown to be associated with a better overall survival than IDH-WT tumors, when compared grade for grade, and also is associated with a longer time to transformation in LGGs when compared with tumors expressing only the wild type enzymes. Acquired somatically, IDH1 and 2 mutations are activating mutations in the enzyme binding site which leads to production of high levels of 2 hydroxyglutarate (2HG) from ?-ketoglutarate. The functional oncogenic and metabolic consequences of 2HG production have not yet been elucidated but identification of the mutant enzymes has focused intense interest on LGG metabolism and the possibility that alterations in metabolic pathways may underlie cellular transformation, tumor growth and/or transformation to high grade glioma. We have developed methods to study LGG cell metabolism in situ, taking advantage of the stable isotope, 13Carbon (13C). 13C-labeled glucose can be safely infused in patients undergoing surgical resection and then labeled tumor can be analyzed ex vivo by 13C-NMR to probe the metabolic pathways that are active in the cell. This method provides a direct assessment of the impact of an IDH mutation since both the IDH- mutant and IDH-WT tumors reside in the same microenvironment, are histological indistinguishable from each other, and have not been altered by treatment prior to resection. This is a unique experimental paradigm in patients that can be exploited to directly compare the effects of the mutant metabolic enzyme on the metabolic pathways that are important for tumor cell survival and proliferation. To compliment these in situ studies, we have developed a novel method to identify 2HG in IDH-mutated tumors in vivo using non-invasive proton magnetic resonance spectroscopy (1H-MRS) in patients undergoing brain MR imaging for clinical follow up. When combined with molecular analysis of the tumors, these complimentary methods provide an excellent opportunity to greatly improve the understanding of the fundamental metabolic processes in the LGG cell and determine to what extent they are modulated by genotype.
Low grade gliomas (LGG) are primary brain tumors that affect young adults and are uniformly fatal. We propose to combine 13C-nuclear magnetic resonance (NMR) of labeled rejected tumor tissue with non-invasive proton magnetic resonance spectroscopy (1H-MRS) in patients to define the metabolic phenotype of LGGs. The overarching goal is to identify novel therapeutic targets for this disease.
