Abstract 4375: Sunitinib alone and in combination with SN-38 is active against anaplastic thyroid cancer

Abstract

Abstract Background: Anaplastic thyroid cancer (ATC) is the most aggressive thyroid gland malignancy. Recent experimental evidences suggest a rationale for the use of multitarget tyrosine kinase inhibitors (TKIs). Sunitinib showed evidences of activity in a phase I trial in different tumors, including thyroid cancers. TKIs are usually more effective in combination with standard chemotherapy. Among chemotherapeutic drugs, preclinical studies using irinotecan seem to be very promising in different types of thyroid carcinomas. The aim of this study is to determine the activity of sunitinib alone and in combination with irinotecan on endothelial and ATC cells. METHODS: Proliferation and apoptotic assays were performed on human dermal microvascular endothelial cells (HMVEC-d) and ATC (8305C, FB3) cell lines exposed to sunitinib (SU) and SN-38, the active metabolite of irinotecan, for 72h. The synergism was determined with the method by Chou and quantified by the combination index (CI), where CI < 1, CI = 1, and CI > 1 indicates synergism, additive effect, and antagonism, respectively. Cell-based phospho-VEGFR-2 assay was performed and ERK1/2 and Akt phosphorylation were quantified by ELISA kits. Cyclin D1 and CDK2 gene expression were performed with real-time PCR and cyclin D1 intracellular concentrations were measured by ELISA. 8305C xenografts in nude mice were treated with sunitinib (50 mg/kg/day) and tumour volumes were measured. RESULTS: A strong antiproliferative and pro-apoptotic activities were determined by SU on both endothelial and cancer cells, synergistically enhanced by SN38. Phospho-VEGFR-2 levels significantly decreased after SU treatments in activated endothelial cells; ERK1/2 and Akt phosphorylation was significantly inhibited by SU in endothelial and cancer cells, although at lower concentrations in the endothelial ones. Moreover, SU treatment greatly inhibited the expression of the cyclin D1 and CDK2 genes in both endothelial and cancer cells, decreasing the cyclin D1 protein intracellular concentration. In vivo administration of sunitinib was effective and determined a significant tumor regression. CONCLUSIONS: SU demonstrated a highly significant antiproliferative and proapoptotic activity, for activated endothelial and ATC cells. Moreover, the simultaneous combination of sunitinib and irinotecan determined a high synergism on endothelial and ATC cells, suggesting a possible translation of this schedule into the clinics. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4375. doi:1538-7445.AM2012-4375