title: 18F-FET microPET and microMRI for anti-VEGF and anti-PlGF response assessment in an orthotopic murine model of human glioblastoma.
abstract: BACKGROUND
  Conflicting data exist for anti-cancer effects of anti-placental growth factor (anti-PlGF) in combination with anti-VEGF. Still, this treatment combination has not been evaluated in intracranial glioblastoma (GBM) xenografts. In clinical studies, position emission tomography (PET) using the radiolabeled amino acid O-(2-18F-fluoroethyl)-L-tyrosine (18F-FET) and magnetic resonance imaging (MRI) add complementary but distinct information about glioma growth; however, the value of 18F-FET MicroPET combined with MicroMRI has not been investigated preclinically. Here we examined the use of 18F-FET MicroPET and MicroMRI for evaluation of anti-VEGF and anti-PlGF treatment response in GBM xenografts.
  
  
  METHODS
  Mice with intracranial GBM were treated with anti-VEGF, anti-PlGF + anti-VEGF or saline. Bioluminescence imaging (BLI), 18F-FET MicroPET and T2-weighted (T2w)-MRI were used to follow tumour development. Primary end-point was survival, and tumours were subsequently analysed for Ki67 proliferation index and micro-vessel density (MVD). Further, PlGF and VEGFR-1 expression were examined in a subset of the xenograft tumours and in 13 GBM patient tumours.
  
  
  RESULTS
  Anti-VEGF monotherapy increased survival and decreased 18F-FET uptake, BLI and MVD, while no additive effect of anti-PlGF was observed. 18F-FET SUV max tumour-to-brain (T/B) ratio was significantly lower after one week (114 ± 6%, n = 11 vs. 143 ± 8%, n = 13; p = 0.02) and two weeks of treatment (116 ± 12%, n = 8 vs. 190 ± 24%, n = 5; p = 0.02) in the anti-VEGF group as compared with the control group. In contrast, T2w-MRI volume was unaffected by anti-VEGF. Gene expression of PlGF and VEGFR-1 in xenografts was significantly lower than in patient tumours.
  
  
  CONCLUSIONS
  18F-FET PET was feasible for anti-angiogenic response evaluation and superior to T2w-MRI; however, no additive anti-cancer effect of anti-PlGF and anti-VEGF was observed. Thus, this study supports use of 18F-FET PET for response evaluation in future studies.
authors: Department of Clinical Physiology, Nuclear Medicine & PET and Cluster for Molecular Imaging, Rigshospitalet and University of Copenhagen, Copenhagen, Denmark.
authors: Mette Kjoelhede
authors: MK
authors: Nedergaard
authors: Department of Radiation Biology, The Finsen Center, Rigshospitalet, Copenhagen, Denmark.
authors: Signe Regner
authors: SR
authors: Michaelsen
authors: Department of Radiation Biology, The Finsen Center, Rigshospitalet, Copenhagen, Denmark.
authors: Thomas
authors: T
authors: Urup
authors: Department of Neuropathology, Center of Diagnostic Investigation, Rigshospitalet, Copenhagen, Denmark.
authors: Helle
authors: H
authors: Broholm
authors: Department of Clinical Physiology, Nuclear Medicine & PET and Cluster for Molecular Imaging, Rigshospitalet and University of Copenhagen, Copenhagen, Denmark.
authors: Henrik
authors: H
authors: El Ali
authors: Department of Radiation Biology, The Finsen Center, Rigshospitalet, Copenhagen, Denmark.
authors: Hans Skovgaard
authors: HS
authors: Poulsen
authors: Department of Radiation Biology, The Finsen Center, Rigshospitalet, Copenhagen, Denmark.
authors: Marie-Thérése
authors: MT
authors: Stockhausen
authors: Department of Clinical Physiology, Nuclear Medicine & PET and Cluster for Molecular Imaging, Rigshospitalet and University of Copenhagen, Copenhagen, Denmark.
authors: Andreas
authors: A
authors: Kjaer
authors: Phase 1 Unit, Department of Oncology, The Finsen Center, Rigshospitalet, Copenhagen, Denmark.
authors: Ulrik
authors: U
authors: Lassen
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D000971:Antineoplastic Combined Chemotherapy Protocols; D001932:Brain Neoplasms / Q000175:diagnosis / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic; D004357:Drug Synergism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D005909:Glioblastoma / Q000175:diagnosis / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D006801:Humans; D008279:Magnetic Resonance Imaging; D008565:Membrane Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics; D051379:Mice; D055806:Microvessels / Q000187:drug effects; D064847:Multimodal Imaging; D061848:Optical Imaging; D049268:Positron-Emission Tomography; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D016019:Survival Analysis; D014057:Tomography, X-Ray Computed; D016896:Treatment Outcome; D014443:Tyrosine / Q000031:analogs & derivatives*; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors*; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000235:genetics
chemical_list: D000970:Antineoplastic Agents; D008565:Membrane Proteins; C098069:PIGF protein, human; D012333:RNA, Messenger; D042461:Vascular Endothelial Growth Factor A; C545932:(18F)fluoroethyltyrosine; D014443:Tyrosine; D040281:Vascular Endothelial Growth Factor Receptor-1