title: Measurement of tumor VEGF-A levels with 89Zr-bevacizumab PET as an early biomarker for the antiangiogenic effect of everolimus treatment in an ovarian cancer xenograft model.
abstract: OBJECTIVE
  The mTOR pathway is frequently activated in ovarian cancers. mTOR inhibitors, such as everolimus, can reduce VEGF-A production by cancer cells. We investigated whether early everolimus treatment effects could be monitored by positron emission tomography (PET) with (89)Zr-bevacizumab.
  
  
  METHODS
  The effect of everolimus on VEGF-A secretion was determined in a panel of human ovarian cancer cell lines and in A2780(luc+) ovarian cancer cells xenografted subcutaneously in BALB/c mice. Mice received daily 10 mg/kg everolimus intraperitoneally (i.p.) for 14 days. PET scans with the tracer (89)Zr-labeled bevacizumab were conducted before and after treatment. Ex vivo (89)Zr-bevacizumab biodistribution and correlative tissue analyses were conducted. Tumor VEGF-A levels were measured with ELISA and mean vascular density (MVD) was determined with immunohistochemistry.
  
  
  RESULTS
  Everolimus treatment reduced VEGF-A levels in the supernatant of all cell lines. Everolimus lowered (89)Zr-bevacizumab tumor uptake by 21.7% ± 4.0% [mean standardized uptake value (SUV(mean)) 2.3 ± 0.2 vs. 2.9 ± 0.2, P < 0.01]. Ex vivo biodistribution also showed lower tracer uptake in the tumors of treated as compared with control animals (7.8 ± 0.8%ID/g vs. 14.0 ± 1.7%ID/g, P < 0.01), whereas no differences were observed for other tissues. This coincided with lower VEGF-A protein levels in tumor lysates in treated versus untreated tumors (P = 0.04) and reduced MVD (P < 0.01).
  
  
  CONCLUSIONS
  Tumor VEGF-A levels are decreased by everolimus. (89)Zr-bevacizumab PET could be used to monitor tumor VEGF-A levels as an early biomarker of the antiangiogenic effect of mTOR inhibitor therapy.
authors.affiliation: Department of Medical Oncology, Hospital and Clinical Pharmacy, and Nuclear Medicine and Molecular Imaging, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: Arne R M
authors.initials: AR
authors.lastname: van der Bilt
authors.forename: Anton G T
authors.initials: AG
authors.lastname: Terwisscha van Scheltinga
authors.forename: Hetty
authors.initials: H
authors.lastname: Timmer-Bosscha
authors.forename: Carolien P
authors.initials: CP
authors.lastname: Schröder
authors.forename: Linda
authors.initials: L
authors.lastname: Pot
authors.forename: Jos G W
authors.initials: JG
authors.lastname: Kosterink
authors.forename: Ate G J
authors.initials: AG
authors.lastname: van der Zee
authors.forename: Marjolijn N
authors.initials: MN
authors.lastname: Lub-de Hooge
authors.forename: Steven
authors.initials: S
authors.lastname: de Jong
authors.forename: Elisabeth G E
authors.initials: EG
authors.lastname: de Vries
authors.forename: Anna K L
authors.initials: AK
authors.lastname: Reyners
mesh_terms: D020533:Angiogenesis Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000493:pharmacokinetics; D000068258:Bevacizumab; D014408:Biomarkers, Tumor / Q000378:metabolism; D045744:Cell Line, Tumor; D000068338:Everolimus; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D010051:Ovarian Neoplasms / Q000098:blood supply / Q000000981:diagnostic imaging* / Q000188:drug therapy / Q000378:metabolism; D049268:Positron-Emission Tomography; D011868:Radioisotopes; D019275:Radiopharmaceuticals / Q000493:pharmacokinetics; D020123:Sirolimus / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays; D015040:Zirconium
chemical_list: D020533:Angiogenesis Inhibitors; D061067:Antibodies, Monoclonal, Humanized; D014408:Biomarkers, Tumor; D011868:Radioisotopes; D019275:Radiopharmaceuticals; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D000068258:Bevacizumab; D000068338:Everolimus; C580636:89Zr-bevacizumab; D015040:Zirconium; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus