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Research Articles: Therapeutics, Targets, and Development

Targeted therapy of orthotopic human lung cancer by combined vascular endothelial growth factor and epidermal growth factor receptor signaling blockade

Departments of ¹ Thoracic/Head and Neck Medical Oncology, ² Pulmonary Medicine, ³ Cancer Biology, and ⁴ Radiation Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas and ⁵ AstraZeneca, Macclesfield, United Kingdom

Requests for reprints: Michael S. O'Reilly, Department of Radiation Oncology, The University of Texas M. D. Anderson Cancer Center, Unit 97, 1515 Holcombe Boulevard, Houston, TX 77030. Phone: 713-563-2300; Fax: 713-563-2331. E-mail: moreilly{at}mdanderson.org

Abstract

The outcome for patients with lung cancer has not changed significantly for more than two decades. Several studies show that the overexpression of vascular endothelial growth factor (VEGF)/vascular permeability factor and epidermal growth factor (EGF) and their receptors correlates with the clinical outcome for lung cancer patients. However, clinical trials of agents that target either of these pathways alone have been disappointing. We hypothesize that targeting both the tumor and its vasculature by simultaneously blocking the VEGFR and EGFR pathways will improve the treatment of locoregional lung cancer. Human lung cancer specimens were first examined for the activation of VEGF receptor 2 (VEGFR2) and EGF receptor (EGFR) for tumor and tumor-associated endothelial cells, and both were found to be activated. The effects of ZD6474 (ZACTIMA), a small-molecule inhibitor of VEGFR2 and EGFR tyrosine kinases, were then studied in vitro using human lung cancer and microvascular endothelial cells. In vitro, ZD6474 inhibited EGFR, VEGFR2, mitogen-activated protein kinase and Akt phosphorylation, EGF- and VEGF-induced proliferation, and endothelial cell tube formation and also induced apoptosis. ZD6474 was further studied in vivo using an orthotopic mouse model of non–small cell lung cancer using NCI-H441 human lung adenocarcinoma cells. The inhibition of both VEGFR2 and EGFR signaling pathways by ZD6474 resulted in profound antiangiogenic, antivascular, and antitumor effects. These results provide a basis for the development of clinical strategies for the combination of selective protein tyrosine kinase inhibitors that block both EGFR and VEGFR signaling as part of the management of locally advanced lung cancer. [Mol Cancer Ther 2007;6(2):471–83]

Grant support: The University of Texas M. D. Anderson Cancer Center Physician Scientist Program Awards (M.S. O'Reilly and R.S. Herbst), Department of Defense grant DAMD 17-02-1-0706, and AstraZeneca.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Received 7/17/06; revised 11/ 1/06; accepted 12/20/06.

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