BI-10 * pH-WEIGHTED MRI IN HUMAN GLIOMAS

Abstract

Regions of proliferating tumor are characterized by extracellular acidosis and hypoxia. Additionally, tumor cells utilize glutamine and other amino acids for fuel, resulting in elevated extracellular concentrations of glutamine in areas of metabolically active tumor. In the current study we explore the use of chemical exchange saturation transfer (CEST) MRI targeting exchangeable protons on the amine functional group in free amino acids as a pH-weighted imaging biomarker for non-invasively identifying regions of low pH, suggestive of regions with active tumor. The dependence of CEST contrast on pH was measured for three amino acids, and the dependence of CEST contrast on metabolite concentration was measured for glutamine. CEST data was collected in a cohort of twelve GBM patients undergoing radiochemotherapy. CEST data and corresponding histology were collected in a patient with suspected low grade glioma and a GBM patient at tumor recurrence. Results show a sigmoidal relationship between CEST contrast and pH within a range of 5.0-8.0. CEST contrast increased with both decreasing pH and increasing amino acid concentration, and the three amino acids produced similar CEST signatures within a physiologically relevant range of pH (6.0-7.0). Clinically, some patients who showed elevated CEST contrast in the tumor region appeared to show an increase in tumor volume at six months post-treatment, while a patient who did not show elevated CEST contrast in the tumor region appeared to show a slight decrease in tumor volume at six months post-treatment. In biopsy patients, regions of CEST contrast suggestive of low pH and active tumor correctly identified proliferative tumor, while areas suggestive of normal pH showed gliosis. In summary, results suggest CEST imaging of the amine functional group on free amino acids is sensitive to acidic pH and elevated amino acid concentration, allowing non-invasive identification of metabolically active tumor with a high specificity.