Abstract 4418: ENMD-1198, a new microtubule-targeting agent with potent anti-vascular properties

Proceedings: AACR 101st Annual Meeting 2010‐‐ Apr 17‐21, 2010; Washington, DC The formation of a new vascular network, by a process called angiogenesis, is a key driver in tumor growth and metastasis, making this an attractive therapeutic target in the fight against cancer. Different strategies are being developed to either prevent tumor angiogenesis (anti-angiogenic therapy) or disrupt the tumor vasculature already in place (vascular-disrupting therapy). ENMD-1198 is a new analogue of 2-methoxyestradiol (2-ME2), a microtubule-targeting agent that has shown promising results in the treatment of multiple myeloma, hormone refractory prostate cancer and recurrent ovarian cancer. Pre-clinical in vivo studies have shown that ENMD-1198 displayed improved metabolic stability as compared to its parental compound (2-ME2) and retained potent anti-tumor activity [1, 2]. We hypothesized that ENMD-1198 may also exhibit improved anti-angiogenic and/or vascular-disrupting properties. Using both bone-marrow derived and dermal microvascular endothelial cell lines, we thus analyzed and compared the effects of ENMD-1198 and 2-ME2 on the different functions of endothelial cells involved in angiogenesis. In both cell lines, ENMD-1198 was more potent than 2-ME2 at inhibiting endothelial cell proliferation, motility, migration and morphogenesis. In addition, videomicroscopy experiments revealed that ENMD-1198 was able to completely disrupt pre-formed vascular structures within 2 hours. This vascular-disrupting activity was associated with extensive depolymerisation of microtubules, accumulation of actin stress fibers and alteration in focal adhesions. Collectively, our results demonstrate that this new compound displays improved anti-vascular properties and this study provides important insights into the mechanism of action of ENMD-1198, a promising new anti-cancer drug. 1. LaVallee T.M, Burke P.A, Swartz G.M et al. (2008) Mol Cancer Ther.7: 1472-82. 2. Moser C., Lang S.A., Mori A. et al. (2008) BMC Cancer 8:206. 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 4418.