Abstract 3614: Multi-targeted kinase inhibitor E7080 showed anti-tumor activity against medullary thyroid carcinoma and squamous thyroid carcinoma cell line based on RET and VEGFR2 tyrosine kinase inhibition

Abstract

Abstract There are about 37,000 and 8,000 new cases of thyroid cancer each year in the US and JP respectively, according to reports of the National Cancer Institute and National Cancer Center in Japan. Thyroid cancer is one of most common cancers after age 30, and its aggressiveness increases significantly in older patients. VEGFR tyrosine kinase inhibitors showed anti-tumor activity against thyroid carcinoma in early clinical study and some of inhibitors have been tested in late stage of clinical trial. E7080, a multi-targeted kinase inhibitor, potently inhibits VEGFR1-3, FGFR1-4 and RET tyrosine kinases and has been tested in several PhII trials including thyroid carcinoma trial. In this study, we report the efficacy of E7080 as an anti-cancer agent for thyroid carcinoma, based on both anti-tumorigenic activity and anti-angiogenic activity. E7080 inhibit RET kinase and VEGFR2 kinase with Ki values of 1.5 and 0.74 nmol/L, respectively, in cell free kinase assays. E7080 inhibited proliferation and phosphorylation of RET as well that of downstream Erk1/2 in medullary thyroid carcinoma (MTC) cell lines, TT and MTC-M, which expressed RET kinase in a dose dependent manner. E7080 showed significantly anti-tumor activity at the dose of 10-100 mg/kg in TT xenograft and 1-100 mg/kg in MTC xenograft without affecting microvessel density, suggesting that anti-tumor activity was caused by anti-tumorigenic activity based on RET kinase inhibition. On the other hand, E7080 did not show anti-proliferative activity against thyroid squamous carcinoma cell line, SW579, which did not expressed RET kinase, even at 10 µmol/L of E7080. While E7080 significantly inhibited in vivo growth of SW579 tumor in nude mice, accompanied by decreased of microvessel density within xenografted tumors at 3 - 100 mg/kg. These results demonstrated that the blockage of RET and VEGFR2 was a promising therapeutic strategy against several types of thyroid carcinoma and E7080, a dual inhibitor of both VEGFR2 and RET tyrosine kinase, is warranted to be examined for thyroid cancer patients. 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 3614.