title: Epidermal growth factor receptor expression modulates antitumor efficacy of vandetanib or cediranib combined with radiotherapy in human glioblastoma xenografts.
abstract: OBJECTIVE
  The purpose of this study was to determine the ability of radiation therapy (RT) combined with the tyrosine kinase inhibitors (TKI) vandetanib (antiepidermal growth factor receptor [EGFR] plus antivascular endothelial growth factor receptor [anti-VEGFR]) and cediranib (anti-VEGFR) to inhibit glioblastoma multiforme (GBM) growth. A secondary aim was to investigate how this regimen is modulated by tumor EGFR expression.
  
  
  METHODS
  Radiosensitivity was assessed by clonogenic cell survival assay. VEGF secretion was quantified by enzyme-linked immunosorbent assay. GBM (U87MG wild-type EGFR [wtEGFR] and U87MG EGFR-null) xenografts were treated with vandetanib, cediranib, and RT, alone or in combinations. Excised tumor sections were stained for proliferative and survival biomarkers.
  
  
  RESULTS
  In vitro, U87MG wtEGFR and U87 EGFR-null cells had similar growth kinetics. Neither TKI affected clonogenic cell survival following RT. However, in vivo, exogenous overexpression of wtEGFR decreased tumor doubling time (T2x) in U87MG xenografts (2.70 vs. 4.41 days for U87MG wtEGFR vs. U87MG vector, respectively). In U87MG EGFR-null cells, TKI combined with radiation was no better than radiation therapy alone. In U87MG wtEGFR, RT in combination with vandetanib (but not with cediranib) significantly increased tumor T2x compared with RT alone (T2x, 10.4 days vs. 4.8 days; p < 0.001). In vivo, growth delay correlated with suppression of pAkt, survivin, and Ki67 expression in tumor samples. The presence of EGFR augmented RT-stimulated VEGF release; this effect was inhibited by vandetanib.
  
  
  CONCLUSIONS
  EGFR expression promoted tumor growth in vivo but not in vitro, suggesting a microenvironmental effect. GBM xenografts expressing EGFR exhibited greater sensitivity to both cediranib and vandetanib than EGFR-null tumors. Hence EGFR status plays a major role in determining a tumor's in vivo response to radiation combined with TKI, supporting a "personalized" approach to GBM management.
authors.affiliation: Department of Radiation Oncology, Thomas Jefferson University, Philadelphia, Pennsylvania 19107, USA. Phyllis.wachsberger@jeffersonhospital.org
authors.forename: Phyllis R
authors.initials: PR
authors.lastname: Wachsberger
authors.forename: Yaacov R
authors.initials: YR
authors.lastname: Lawrence
authors.forename: Yi
authors.initials: Y
authors.lastname: Liu
authors.forename: Borbala
authors.initials: B
authors.lastname: Daroczi
authors.forename: Xia
authors.initials: X
authors.lastname: Xu
authors.forename: Adam P
authors.initials: AP
authors.lastname: Dicker
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D014408:Biomarkers, Tumor / Q000378:metabolism; D045744:Cell Line, Tumor; D059248:Chemoradiotherapy / Q000379:methods; D004334:Drug Administration Schedule; D066246:ErbB Receptors / Q000378:metabolism*; D005909:Glioblastoma / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009363:Neoplasm Proteins / Q000378:metabolism*; D010880:Piperidines / Q000627:therapeutic use*; D011799:Quinazolines / Q000627:therapeutic use*; D011836:Radiation Tolerance; D040262:Receptors, Vascular Endothelial Growth Factor / Q000037:antagonists & inhibitors*; D047368:Tumor Burden; D023041:Xenograft Model Antitumor Assays; D007211:Indoles
chemical_list: D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D066246:ErbB Receptors; D009363:Neoplasm Proteins; D010880:Piperidines; D011799:Quinazolines; D040262:Receptors, Vascular Endothelial Growth Factor; C500926:cediranib; D007211:Indoles; C452423:vandetanib