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Research Articles: Therapeutics, Targets, and Development

Potent antitumor effects of ZD6474 on neuroblastoma via dual targeting of tumor cells and tumor endothelium

¹ Department of Vascular Biology, Boston Children's Hospital, Boston, Massachusetts; ² Department of Surgery, Alberta Children's Hospital, Calgary, Alberta, Canada; Departments of ³ Cancer Biology, ⁴ Pediatrics, and ⁵ Thoracic/Head and Neck Medical Oncology, University of Texas M. D. Anderson Cancer Center, Houston, Texas; and ⁶ Astra Zeneca, Macclesfield, Cheshire, United Kingdom

Requests for reprints: Paul Beaudry, Department of Surgery, Alberta Children's Hospital, 2888 Shaganappi Trail Northwest, Calgary, Alberta, Canada T3B 6A8. Phone: 403-955-2850. E-mail: Paul.Beaudry{at}CalgaryHealthRegion.ca

Abstract

Among children with relapsed or refractory neuroblastoma, the prognosis is poor and novel therapeutic strategies are needed to improve long-term survival. As with other solid tumors, high vascular density within neuroblastoma is associated with advanced disease, and therapeutic regimens directed against the tumor vasculature may provide clinical benefit. The receptor tyrosine kinase RET is widely expressed in neuroblastoma and is known to activate key signal transduction pathways involved in tumor cell survival and progression including Ras/mitogen-activated protein kinase and phosphatidylinositol 3-kinase/Akt. We investigated the effect of dual targeting of tumor cells and tumor endothelium with ZD6474, a small-molecule tyrosine kinase inhibitor of vascular endothelial growth factor (VEGF) receptor 2, epidermal growth factor receptor, and RET. ZD6474 inhibited the phosphorylation of RET in neuroblastoma cells and had a direct effect on tumor cell viability in seven neuroblastoma cell lines. In a human neuroblastoma xenograft model, ZD6474 inhibited tumor growth by 85% compared with treatment with vehicle alone. In contrast, no significant inhibition of tumor growth was observed after treatment with bevacizumab, an antihuman VEGF monoclonal antibody, or the epidermal growth factor receptor inhibitor erlotinib, either alone or in combination. Immunohistochemical analysis showed that ZD6474 treatment led to an increase in endothelial cell apoptosis along with inhibition of VEGF receptor-2 activation on tumor endothelium. In conclusion, dual targeting of tumor cells, potentially through RET inhibition, and tumor vasculature with ZD6474 leads to potent antitumor effects. This approach merits further investigation for patients with neuroblastoma. [Mol Cancer Ther 2008;7(2):418–24]

Grant support: NIH Specialized Program of Research Excellence grant P20 CA090578 and Howard Hughes Medical Institute Specialized Program of Research Excellence Pilot award (J.V. Heymach). J.V. Heymach is a Damon Runyon-Lilly Clinical Investigator supported in part by Damon Runyon Cancer Research Foundation grant CI 24-04.

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 8/17/07; revised 11/20/07; accepted 12/28/07.