title: 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Corresponding Author: William Leenders, PhD, Dept of Pathology, Radboud University Nijmegen Medical Centre, PO Box 9101, 6500 HB Nijmegen, the Netherlands. w.leenders@pathol.umcn.nl.
authors.forename: Bob
authors.initials: B
authors.lastname: Hamans
authors.forename: Anna Catharina
authors.initials: AC
authors.lastname: Navis
authors.forename: Alan
authors.initials: A
authors.lastname: Wright
authors.forename: Pieter
authors.initials: P
authors.lastname: Wesseling
authors.forename: Arend
authors.initials: A
authors.lastname: Heerschap
authors.forename: William
authors.initials: W
authors.lastname: Leenders
mesh_terms: D020533:Angiogenesis Inhibitors / Q000627:therapeutic use*; D000818:Animals; D001932:Brain Neoplasms / Q000098:blood supply / Q000175:diagnosis* / Q000188:drug therapy; D003287:Contrast Media; D005260:Female; D005910:Glioma / Q000098:blood supply / Q000175:diagnosis* / Q000188:drug therapy; D006019:Glycolysis; D006801:Humans; D000860:Hypoxia; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D007124:Immunoenzyme Techniques; D008279:Magnetic Resonance Imaging; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009389:Neovascularization, Pathologic / Q000175:diagnosis*; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D020533:Angiogenesis Inhibitors; D003287:Contrast Media; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit
keywords: Warburg effect; anti-angiogenic therapy; glioma; magnetic resonance spectroscopic imaging; tumor metabolism