Multivoxel 1H MR spectroscopy is superior to contrast-enhanced MRI for response assessment after anti-angiogenic treatment of orthotopic human glioma xenografts and provides handles for metabolic targeting

Abstract

Background Anti-angiogenic treatment of glioblastoma characteristically results in therapy resistance and tumor progression via diffuse infiltration. Monitoring tumor progression in these patients is thwarted because therapy results in tumor invisibility in contrast-enhanced (CE) MRI. To address this problem, we examined whether tumor progression could be monitored by metabolic mapping using (1)H MR spectroscopic imaging (MRSI). Methods We treated groups of BALB/c nu/nu mice carrying different orthotopic diffuse-infiltrative glioblastoma xenografts with bevacizumab (anti-vascular endothelial growth factor [VEGF] antibody, n = 13), cabozantinib (combined VEGF receptor 2/c-Met tyrosine kinase inhibitor, n = 11), or placebo (n = 15) and compared CE-MRI with MRS-derived metabolic maps before, during, and after treatment. Metabolic maps and CE-MRIs were subsequently correlated to histology and immunohistochemistry. Results In vivo imaging of choline/n-acetyl aspartate ratios via multivoxel MRS is better able to evaluate response to therapy than CE-MRI. Lactate imaging revealed that diffuse infiltrative areas in glioblastoma xenografts did not present with excessive glycolysis. In contrast, glycolysis was observed in hypoxic areas in angiogenesis-dependent compact regions of glioma only, especially after anti-angiogenic treatment. Conclusion Our data present MRSI as a powerful and feasible approach that is superior to CE-MRI and may provide handles for optimizing treatment of glioma. Furthermore, we show that glycolysis is more prominent in hypoxic areas than in areas of diffuse infiltrative growth. The Warburg hypothesis of persisting glycolysis in tumors under normoxic conditions may thus not be valid for diffuse glioma.