University of Kentucky Center for Cancer and Metabolism (Pilot Project - Dr. John Villano)

Gilomas are the most common primary brain tumor, with a clinical behavior based on molecular profiling, the most important is isocitrate dehydrogenase (IDH) mutations. This pilot project seeks to determine the metabolic consequences of IDH mutations in gliomas compared with those with wild type enzyme in fresh tumor tissue samples. This mutation produces an onco-metabolite, D-2-hydroxyglutarate (D2HG), a potent inhibitor of 2-oxoglutarate (2OG) dependent dioxygenases that have demonstrated a role in oxidative stress, lipid metabolism, and HIF1A stability. Metabolic studies of gliomas have not used primary fresh tumor tissue for analysis. Pre-clinical data from explants in mice suggests a dependency on glutamate and lactate in IDH mutant gliomas, while IDH wildtype are dependent on glucose and glutamine. The metabolic differences may explain the diffuse nature of these cancers and the aggressive behavior of IDH wildtype gliomas. We propose a metabolic analysis by incubating freshly resected glioma tissue with 13C5, 15N2 glutamine in tissue culture using a technique we have established for in our institution, and sample both the medium and the tissue. This is of value as metabolic differences between both subtypes could result in potential therapeutic and preventive markers as well as patient selection and recommendations based entirely on tumor metabolism requirement. These studies include investigation with select IDH inhibitors. We proposed a feasibility study that will allow preliminary data to apply for future NIH funding, that will provide mechanistic basis for practice-changing clinical trials by enhancing glutaminolysis in IDH mutant gliomas.