title: Gefitinib selectively inhibits tumor cell migration in EGFR-amplified human glioblastoma.
abstract: BACKGROUND
  Tissue invasion is a hallmark of most human cancers and remains a major source of treatment failure in patients with glioblastoma (GBM). Although EGFR amplification has been previously associated with more invasive tumor behavior, existing experimental models have not supported quantitative evaluation of interpatient differences in tumor cell migration or testing of patient-specific responses to therapies targeting invasion. To explore these questions, we optimized an ex vivo organotypic slice culture system allowing for labeling and tracking of tumor cells in human GBM slice cultures.
  
  
  METHODS
  With use of time-lapse confocal microscopy of retrovirally labeled tumor cells in slices, baseline differences in migration speed and efficiency were determined and correlated with EGFR amplification in a cohort of patients with GBM. Slices were treated with gefitinib to evaluate anti-invasive effects associated with targeting EGFR.
  
  
  RESULTS
  Migration analysis identified significant patient-to-patient variation at baseline. EGFR amplification was correlated with increased migration speed and efficiency compared with nonamplified tumors. Critically, gefitinib resulted in a selective and significant reduction of tumor cell migration in EGFR-amplified tumors.
  
  
  CONCLUSIONS
  These data provide the first identification of patient-to-patient variation in tumor cell migration in living human tumor tissue. We found that EGFR-amplified GBM are inherently more efficient in their migration and can be effectively targeted by gefitinib treatment. These data suggest that stratified clinical trails are needed to evaluate gefitinib as an anti-invasive adjuvant for patients with EGFR-amplified GBM. In addition, these results provide proof of principle that primary slice cultures may be useful for patient-specific screening of agents designed to inhibit tumor invasion.
authors.affiliation: Medical Scientist Training Program, University of Colorado, School of Medicine, Anschutz Medical Campus, Aurora, CO, USA.
authors.forename: Jonathon J
authors.initials: JJ
authors.lastname: Parker
authors.forename: Kalen R
authors.initials: KR
authors.lastname: Dionne
authors.forename: Rada
authors.initials: R
authors.lastname: Massarwa
authors.forename: Marci
authors.initials: M
authors.lastname: Klaassen
authors.forename: Nicholas K
authors.initials: NK
authors.lastname: Foreman
authors.forename: Lee
authors.initials: L
authors.lastname: Niswander
authors.forename: Peter
authors.initials: P
authors.lastname: Canoll
authors.forename: B K
authors.initials: BK
authors.lastname: Kleinschmidt-Demasters
authors.forename: Allen
authors.initials: A
authors.lastname: Waziri
mesh_terms: D002465:Cell Movement / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects; D015331:Cohort Studies; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000235:genetics*; D000077156:Gefitinib; D005784:Gene Amplification; D005909:Glioblastoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D009924:Organ Culture Techniques; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011799:Quinazolines / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
chemical_list: D047428:Protein Kinase Inhibitors; D011799:Quinazolines; C512478:EGFR protein, human; D066246:ErbB Receptors; D000077156:Gefitinib
keywords: EGFR; gefitinib; glioblastoma; invasion; migration; personalized therapy; slice culture