Abstract 4505: Development of small molecules to target ezrin as anti-metastatic agents

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Abstract The most common cause for mortality in osteosarcoma (OS) is respiratory failure due to metastasis to lungs. Thus targeting underlying molecular events that lead to metastasis can provide a significant benefit to patients with fatal metastatic disease. Accumulating evidence from experimental animal models and human cases suggests that ezrin is a key factor in the metastasis of OS cells. Ezrin is a multifunctional protein that connects the actin cytoskeleton to extracellular matrix through transmembrane proteins. We screened small molecule libraries for compounds that directly interact with ezrin protein. Two small molecules that directly bind to ezrin with low micromolar affinity were selected based on inhibiting ezrin function in multiple assays. They inhibited ezrin phosphorylation, ezrin-actin interaction, and ezrin mediated motility of OS cells in culture. These compounds were unique in their mechanism of action such that they inhibited in vitro phosphorylation of ezrin by protein kinase C (PKC) by binding to the substrate not by inhibiting the kinase activity of the enzyme. PKC was able to phosphorylate other substrates in the presence of these novel ezrin inhibitors. They also mimicked the ezrin morpholino phenotype and caused a unique developmental defect consistent with reduced cell motility in zebrafish. Following tail vein injection of osteosarcoma cells to mice, both molecules inhibited lung metastasis of ezrin-sensitive cells, but not ezrin-resistant cells. These two molecules demonstrate a novel targeted therapy that directly inhibits ezrin protein as an approach to prevent tumor metastasis in osteosarcoma and other tumors with elevated ezrin in their metastatic subclones. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4505. doi:10.1158/1538-7445.AM2011-4505