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Research Articles: Therapeutics, Targets, and Development

Sorafenib inhibits the angiogenesis and growth of orthotopic anaplastic thyroid carcinoma xenografts in nude mice

Departments of ¹ Head and Neck Surgery, ² Pathology, and ³ Cancer Biology, The University of Texas M. D. Anderson Cancer Center and ⁴ Department of Otolaryngology-Head and Neck Surgery, Baylor College of Medicine, Houston, Texas

Requests for reprints: Jeffrey N. Myers, Department of Head and Neck Surgery, The 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

Abstract

Anaplastic thyroid carcinoma (ATC) remains one of the most lethal human cancers. We hypothesized that sorafenib, a multikinase inhibitor of the BRaf, vascular endothelial growth factor receptor-2, and platelet-derived growth factor receptor-ß kinase, would decrease tumor growth and angiogenesis in an orthotopic model of ATC. The in vitro antiproliferative and proapoptotic effects of sorafenib on ATC cell lines were examined. To study the in vivo effects of sorafenib on orthotopic ATC tumors in nude mice, sorafenib was given p.o. at 40 or 80 mg/kg daily. Intratumoral effects were studied using immunohistochemical analysis. The effect of sorafenib on survival of the mice was also studied. Sorafenib inhibited the in vitro proliferation of ATC cell lines. Sorafenib also significantly inhibited tumor angiogenesis via the induction of endothelial apoptosis in an orthotopic model of thyroid cancer. As result, the growth of orthotopic ATC xenografts was reduced and the survival of the test animals was improved. Sorafenib exerts significant antitumor activity in an orthotopic xenograft model of ATC via a potent antiangiogenic effect. The antiangiogenic effects of sorafenib suggest that its use in clinical setting may not depend on the BRAF mutational status of thyroid tumors. Given the lack of curative options for patients with ATC, sorafenib warrants further study as a therapeutic agent against ATC. [Mol Cancer Ther 2007;6(6):1785–92]

Grant support: M. D. Anderson Cancer Center Specialized Programs in Research Excellence in Head and Neck Cancer grant P50 CA097007A, NIH Cancer Center Support grant CA016672, The University of Texas M.D. Anderson Cancer Center PANTHEON Program, National Cancer Institute grants CA 46523 and U01 CA105345, and National Institute of Environmental Health Sciences Center grant ES07784.

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.

Note: Current address for S. Kim: Department of Otolaryngology-Head and Neck Surgery, University of Pittsburgh, Suite 521, 200 Lothrop Street, Pittsburgh, PA 15213.

Received 9/26/06; revised 12/21/06; accepted 4/13/07.