title: Multimodality molecular imaging of glioblastoma growth inhibition with vasculature-targeting fusion toxin VEGF121/rGel.
abstract: Vascular endothelial growth factor A (VEGF-A) and its receptors, Flt-1/FLT-1 (VEGFR-1) and Flk-1/KDR (VEGFR-2), are key regulators of tumor angiogenesis and tumor growth. The purpose of this study was to determine the antiangiogenic and antitumor efficacies of a vasculature-targeting fusion toxin (VEGF(121)/rGel) composed of the VEGF-A isoform VEGF(121) linked with a G(4)S tether to recombinant plant toxin gelonin (rGel) in an orthotopic glioblastoma mouse model by use of noninvasive in vivo bioluminescence imaging (BLI), MRI, and PET.
  
  
  METHODS
  Tumor-bearing mice were randomized into 2 groups and balanced according to BLI and MRI signals. PET with (64)Cu-1,4,7,10-tetraazacyclododedane-N,N',N'',N'''-tetraacetic acid (DOTA)-VEGF(121)/rGel was performed before VEGF(121)/rGel treatment. (18)F-Fluorothymidine ((18)F-FLT) scans were obtained before and after treatment to evaluate VEGF(121)/rGel therapeutic efficacy. In vivo results were confirmed with ex vivo histologic and immunohistochemical analyses.
  
  
  RESULTS
  Logarithmic transformation of peak BLI tumor signal intensity revealed a strong correlation with MRI tumor volume (r = 0.89, n = 14). PET with (64)Cu-DOTA-VEGF(121)/rGel before treatment revealed a tumor accumulation (mean +/- SD) of 11.8 +/- 2.3 percentage injected dose per gram at 18 h after injection, and the receptor specificity of the tumor accumulation was confirmed by successful blocking of the uptake in the presence of an excess amount of VEGF(121). PET with (18)F-FLT revealed significant a decrease in tumor proliferation in VEGF(121)/rGel-treated mice compared with control mice. Histologic analysis revealed specific tumor neovasculature damage after treatment with 4 doses of VEGF(121)/rGel; this damage was accompanied by a significant decrease in peak BLI tumor signal intensity.
  
  
  CONCLUSIONS
  The results of this study suggest that future clinical multimodality imaging and therapy with VEGF(121)/rGel may provide an effective means to prospectively identify patients who will benefit from VEGF(121)/rGel therapy and then stratify, personalize, and monitor treatment to obtain optimal survival outcomes.
authors.affiliation: The Molecular Imaging Program at Stanford, Department of Radiology and Bio-X Program, Stanford University School of Medicine, Stanford, California 94305-5484, USA.
authors.forename: Andrew R
authors.initials: AR
authors.lastname: Hsu
authors.forename: Weibo
authors.initials: W
authors.lastname: Cai
authors.forename: Anand
authors.initials: A
authors.lastname: Veeravagu
authors.forename: Khalid A
authors.initials: KA
authors.lastname: Mohamedali
authors.forename: Kai
authors.initials: K
authors.lastname: Chen
authors.forename: Sehoon
authors.initials: S
authors.lastname: Kim
authors.forename: Hannes
authors.initials: H
authors.lastname: Vogel
authors.forename: Lewis C
authors.initials: LC
authors.lastname: Hou
authors.forename: Victor
authors.initials: V
authors.lastname: Tse
authors.forename: Michael G
authors.initials: MG
authors.lastname: Rosenblum
authors.forename: Xiaoyuan
authors.initials: X
authors.lastname: Chen
mesh_terms: D000818:Animals; D001812:Blood-Brain Barrier; D003301:Copper Radioisotopes; D015224:Dideoxynucleosides; D005909:Glioblastoma / Q000175:diagnosis / Q000188:drug therapy*; D008279:Magnetic Resonance Imaging; D051379:Mice; D010940:Plant Proteins / Q000378:metabolism / Q000627:therapeutic use*; D049268:Positron-Emission Tomography; D040262:Receptors, Vascular Endothelial Growth Factor / Q000032:analysis; D011993:Recombinant Fusion Proteins / Q000378:metabolism / Q000627:therapeutic use*; D054789:Ribosome Inactivating Proteins, Type 1; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism / Q000627:therapeutic use*
chemical_list: D003301:Copper Radioisotopes; D015224:Dideoxynucleosides; D010940:Plant Proteins; D011993:Recombinant Fusion Proteins; D054789:Ribosome Inactivating Proteins, Type 1; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; C025674:GEL protein, Gelonium multiflorum; D040262:Receptors, Vascular Endothelial Growth Factor; C002854:alovudine