Deuterium MRI of serine metabolism in mouse models of glioblastoma

Abstract

PURPOSE Serine is a major source of one-carbon units needed for the synthesis of nucleotides and for the production of intramitochondrial NADPH and plays an important role in cancer cell proliferation. The aim of this study was to develop a 2H magnetic resonance spectroscopic imaging method for imaging tumor serine metabolism. METHODS Sequential 2H spectra and spectroscopic images were used to monitor the metabolism of [2,3,3-2H3]serine in patient-derived glioblastoma cells in vitro and in tumors obtained by their orthotopic implantation in mouse brain. RESULTS [14,14-2H2] 5,10-methylene tetrahydrofolate, [2H]glycine, [2H]formate and labelled water were detected in cell suspensions and water labelling in spectroscopic images of tumors. Studies in cells and tumors with variable mitochondrial content and inhibitor studies in cells demonstrated that most of the labelled serine was metabolized in the mitochondria. Water labelling in the cell suspensions was correlated with formate labelling and therefore water labelling observed in tumors could be used to provide a surrogate measure of flux in the pathway of one-carbon metabolism in vivo. CONCLUSION The method has the potential to be used clinically to select patients for treatment with inhibitors of one carbon metabolism and subsequently to detect their early responses to such treatment.