Abstract 1401: Evaluation of vandetanib (ZD6474) and radiation therapy in an orthotopic xenograft model of anaplastic thyroid carcinoma

Abstract

Abstract Purpose/Objective(s): Anaplastic thyroid carcinoma (ATC) is one of the most aggressive human malignancies with patients facing significant morbidity and high mortality rates. Current therapeutic approaches to ATC have limited efficacy, highlighting the critical need for development of additional therapeutic options. Vandetanib (ZD6474) is an orally-available dual-tyrosine kinase inhibitor of vascular endothelial growth factor receptor 2 (VEGFR2) and the epidermal growth factor receptor (EGFR). In this study, we investigated the anti-tumor effects of vandetanib and radiation therapy alone and in combination in an orthotopic xenograft model of anaplastic thyroid carcinoma. Materials/Methods: ATC cells (Hth83; 5×105 cells/5µL RPMI 1640) with a luciferase reporter gene were injected orthotopically into the right thyroid gland of female athymic nude mice. The tumors were allowed to grow for 7-9 days to a volume of 200-300mm3. Animals were randomized into four groups: control, vandetanib, radiation therapy and vandetanib with radiation therapy. Vandetanib was administered at 25 mg/kg daily orally for 3 consecutive days. Radiation therapy was given in 3 Gy fractions for 3 consecutive days. In the combined treatment group, vandetanib was administered prior to radiation therapy. Tumor growth was assessed with in vivo bioluminescence imaging prior to initiating treatment and on a weekly basis. Tumor volumes were measured and calculated when the mice were sacrificed. Response to these treatments was also measured with dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI). Results: Vandetanib or radiation therapy alone inhibited growth of the ATC xenograft tumor, as measured by bioluminescent activity, by 88.35% and 69.24%, respectively. Mean tumor volume decreased by 43.85% and 36.6% for vandetanib and radiation therapy, respectively. The combination of vandetanib with radiation therapy markedly decreased tumor bioluminescent activity by 99.28% and tumor volume by 86.87% when compared to control. DCE-MRI imaging mechanistically confirmed tumor stromal responses to combined treatment, including alterations in vascular permeability and vascular volume fraction. Conclusion: This study demonstrates the utility of an orthotopic xenograft model as a preclinical platform for the assessment of targeted therapeutic approaches for ATC. Quantifiable imaging-based biomarkers from DCE-MRI studies enhance our mechanistic understanding of in vivo tumor responses to various therapeutic approaches. The combination of vandetanib and radiation therapy significantly affected tumor growth and tumor microenvironment characteristics. These results suggest that the combination of vandetanib and radiation therapy may be a novel option in the treatment of ATC. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1401.