Concurrent cetuximab and bevacizumab therapy in a murine orthotopic model of anaplastic thyroid carcinoma

Abstract

Objective: To evaluate the therapeutic efficacy of bevacizumab and cetuximab, alone and in combination, in an orthotopic model of Anaplastic Thyroid Carcinoma (ATC) in athymic nude mice. Study Design and Setting: This was a randomized, controlled in vivo study. Materials and Methods: The ATC cell line, ARO, was used to establish orthotopic xenografts of ATC in athymic nude mice. Mice were randomized to therapy for 4 weeks in one of four treatment groups: placebo, cetuximab, bevacizumab or the combination of cetuximab and bevacizumab. A second study compared the antitumor efficacy of the cetuximab-bevacizumab combination with doxorubicin. In both studies, tumor volumes on completion were measured and compared. Immunohistochemical analysis was performed with antiCD31 and antiproliferating cell nuclear antigen (PCNA) antibodies to assess the in vivo mechanisms of action of these agents. Results: Cetuximab decreased the production of vascular endothelial growth factor by ATC cell lines in vitro. Mean tumor volumes for the control, bevacizumab, cetuximab and combination groups at the end of the in vivo study were 291, 213, 94 and 42 mm³, respectively. The differences in mean tumor volume for the control versus treatment groups were statistically significant. Immunohistochemical analysis showed decreased microvessel density and PCNA positivity in the treatment groups. In the doxorubicin comparison study, mean tumor volumes for control, doxorubicin and combination antibody treatment groups were 175, 162, and 22 mm³, respectively. Conclusions: Cetuximab and bevacizumab alone and in combination inhibit tumor growth and angiogenesis in an in vivo model of ATC. Also, this therapy was superior to doxorubicin therapy.