Targeted therapy against VEGFR and EGFR with ZD6474 enhances the therapeutic efficacy of irradiation in an orthotopic model of human non-small-cell lung cancer.
OBJECTIVE
Conventional therapies for patients with lung cancer have reached a therapeutic plateau. We therefore evaluated the feasibility of combined vascular endothelial growth factor (VEGF) receptor 2 (VEGFR2) and epidermal growth factor (EGF) receptor (EGFR) targeting with radiation therapy in an orthotopic model that closely recapitulates the clinical presentation of human lung cancer.


METHODS
Effects of irradiation and/or ZD6474, a small-molecule inhibitor of VEGFR2 and EGFR tyrosine kinases, were studied in vitro for human lung adenocarcinoma cells by using proliferation and clonogenic assays. The feasibility of combining ZD6474 with radiation therapy was then evaluated in an orthotopic model of human lung adenocarcinoma. Lung tumor burden and spread within the thorax were assessed, and tumor and adjacent tissues were analyzed by means of immunohistochemical staining for multiple parameters, including CD31, VEGF, VEGFR2, EGF, EGFR, matrix metalloproteinase-2 and -9, and basic fibroblast growth factor.


RESULTS
ZD6474 enhanced the radioresponse of NCI-H441 human lung adenocarcinoma cells by a factor of 1.37 and markedly inhibited sublethal damage repair. In vivo, the combined blockade of VEGFR2 and EGFR by ZD6474 blocked pleural effusion formation and angiogenesis and enhanced the antivascular and antitumor effects of radiation therapy in the orthotopic human lung cancer model and was superior to chemoradiotherapy.


CONCLUSIONS
When radiation therapy is combined with VEGFR2 and EGFR blockade, significant enhancement of antiangiogenic, antivascular, and antitumor effects are seen in an orthotopic model of lung cancer. These data provide support for clinical trials of biologically targeted and conventional therapies for human lung cancer.
Shibuya
Keiko
K
Department of Radiation Oncology, MD Anderson Cancer Center, Houston, TX 77030, USA.
Komaki
Ritsuko
R
Shintani
Tomoaki
T
Itasaka
Satoshi
S
Ryan
Anderson
A
Jürgensmeier
Juliane M
JM
Milas
Luka
L
Ang
Kian
K
Herbst
Roy S
RS
O'Reilly
Michael S
MS
D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D003131:Combined Modality Therapy / Q000379:methods; D004260:DNA Repair / Q000187:drug effects; D004815:Epidermal Growth Factor / Q000378:metabolism; D066246:ErbB Receptors / Q000037:antagonists & inhibitors*; D005240:Feasibility Studies; D006801:Humans; D008175:Lung Neoplasms / Q000098:blood supply / Q000378:metabolism / Q000532:radiotherapy*; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009389:Neovascularization, Pathologic / Q000517:prevention & control*; D010880:Piperidines / Q000627:therapeutic use*; D010996:Pleural Effusion / Q000517:prevention & control; D011799:Quinazolines / Q000627:therapeutic use*; D011836:Radiation Tolerance / Q000187:drug effects; D011838:Radiation-Sensitizing Agents / Q000627:therapeutic use; D040262:Receptors, Vascular Endothelial Growth Factor / Q000037:antagonists & inhibitors; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors*; D023041:Xenograft Model Antitumor Assays
D010880:Piperidines; D011799:Quinazolines; D011838:Radiation-Sensitizing Agents; D042461:Vascular Endothelial Growth Factor A; D004815:Epidermal Growth Factor; D066246:ErbB Receptors; D040262:Receptors, Vascular Endothelial Growth Factor; D040301:Vascular Endothelial Growth Factor Receptor-2; C452423:vandetanib