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Departments of ¹ Head and Neck Surgery, ² Biostatistics and Applied Mathematics, and ³ Cancer Biology, University of Texas M.D. Anderson Cancer Center, Houston, Texas

Requests for reprints: Jeffrey N. Myers, Department of Head and Neck Surgery, University of Texas M.D. Anderson Cancer Center, Unit 441, 1515 Holcombe Boulevard, Houston, TX 77030-4009. Phone: 713-792-6920; Fax: 713-794-4662. E-mail: jmyers{at}mdanderson.org

Anaplastic thyroid carcinoma (ATC) is one of the most aggressive human malignancies with a mean survival of only 6 months. The poor prognosis of patients with ATC reflects the current lack of curative therapeutic options and the need for development of novel therapeutic strategies. In this study, we report the results of a preclinical study of AEE788, a dual inhibitor of epidermal growth factor receptor (EGFR) and vascular endothelial growth factor receptor (VEGFR) tyrosine kinases, against ATC. AEE788 was able to inhibit the proliferation and induce apoptosis of ATC cell lines in vitro. Administration of AEE788, alone and in combination with paclitaxel, to athymic nude mice bearing s.c. ATC xenografts inhibited the growth of ATC xenografts by 44% and 69%, respectively, compared with the control group. Furthermore, tumors from mice treated with AEE788, alone and in combination with paclitaxel, showed increase in apoptosis of tumor cells by 6- and 8-fold, respectively, compared with the control group. The microvessel density within the ATC xenografts was decreased by >80% in the mice treated with AEE788 alone and in combination with paclitaxel compared with the control group. Lastly, immunofluorescence microscopy showed the inhibition of EGFR autophosphorylation on the tumor cells as well as the inhibition of VEGFR-2 autophosphorylation on tumor endothelium. Considering the fact that curative options seldom exist for patients with ATC, concurrent inhibition of EGFR and VEGFR tyrosine kinases seems to be a valid and promising anticancer strategy for these patients.

Key Words: preclinical study • MAPK • angiogenesis

Grant support: University of Texas M.D. Anderson Cancer Center Specialized Program of Research Excellence in Head and Neck Cancer grant P50 CA097007A and Golfers against Cancer grant (J.N. Myers).

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.

⁴ Unpublished data.

Received 11/ 1/04; revised 1/21/05; accepted 2/21/05.