Abstract 2498: BNC105 is a tubulin polymerization inhibitor that exhibits vascular disruptive activity in renal cancer and causes upregulation in HIF1alpha, HIF2alpha and mTOR

Abstract

Abstract BNC105 is a tubulin polymerization inhibitor. This agent selectively disrupts the vasculature in tumors, and in addition acts as a direct cytotoxic against cancer cells. BNC105 has demonstrated single agent efficacy in a number of cell lines and tumor models, including breast, colon, prostate, brain and lung cancer. We have investigated the activity of BNC105 in renal cancer cell lines and renal tumor xenografts. BNC105 exhibits cytotoxic activity with EC50 values in the range of 1-20nM. A number of other chemotherapeutic and targeted agents exhibit activity that is comparable or considerably lower than BNC105. Furthermore, we investigated the activity of BNC105 in disrupting the vasculature of tumors arising from human renal cancer cell lines. Our investigations included the renal cell lines Caki-1 and A498. Caki-1 cells express the wild type of the VHL gene, whereas A498 cells expresses a non-functional mutant form of VHL. In addition A498 cells do not express HIF1alpha. Somatic mutation of the VHL gene is the most frequent genetic alteration observed in renal cell carcinoma leading to inappropriate accumulation of HIF1alpha and HIF2alpha. Single dose BNC105 treatment of mice bearing tumor xenografts arising from these cell lines resulted in substantial tumor vascular disruption giving rise to large areas of tumor necrosis. Immunohistochemistry analysis revealed that expression of HIF1alpha was dramatically increased following BNC105 treatment in tumors arising from the renal cell line Caki-1. HIF1alpha expression in A498 tumors was restricted to endothelial cells and did not change following BNC105 treatment. HIF2alpha expression was found to be upregulated in cells surrounding areas of BNC105 induced necrosis in both Caki-1 and A498 tumors. These findings suggest that vascular disruption and necrosis caused by BNC105 lead to an angiogenic rebound effect that may contribute to tumor recovery from the vascular disruption insult. Given the key role of mTOR signaling in upregulation of HIF we examined the expression of phosphorylated mTOR in renal tumor xenografts following treatment with BNC105. Expression of phosphorylated mTOR was distinctly upregulated in viable cell zones surrounding tumor VDA-induced necrotic areas in both Caki-1 and A498 tumors. These findings suggest that tumor recovery from the necrotic insult of BNC105 is mediated through upregulation of mTOR activity. The potential benefit of combining BNC105 with mTOR inhibitors on the growth of renal tumors is currently being investigated. 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 2498.