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Osteosarcoma is the predominant primary bone cancer in children with a low survival rate due to pulmonary metastasis. Research on the molecular mechanism driving pulmonary metastasis implicates the cytoskeletal protein ezrin as the critical component of the disease pathology. Ezrin links the actin cytoskeleton to the plasma membrane proteins, and its overexpression is associated with poor survival in patients and increased invasion in osteosarcoma cell lines. We used surface plasmon resonance technology to screen small molecule libraries for compounds directly binding to ezrin. Two molecules, NSC305787 and NSC668394, were chosen based on their ezrin binding affinities and ability to inhibit ezrin in multiple functional, biochemical, cellular, and in vivo assays. To test the anti-metastatic activity of these molecules in vivo, we utilized a tissue-specific transgenic mouse model expressing Cre recombinase to excise the Retinoblastoma (Rb) and p53 tumor suppressor genes in osteoblast progenitor cells. These animals develop spontaneous osteosarcoma with 100% penetrance and high frequency of liver and lung metastases, mimicking human disease. We tested the anti-metastatic potential of ezrin inhibitors that we discovered, NSC305787 and NSC668394, in this clinically relevant mouse model. We started the treatment on one group of animals at 2 months of age before any detectable tumor is present and on a second group of animals only after detection of smallest palpable tumor. Animals in each group were randomly assigned to one of three treatment options: DMSO (Control), NSC305787, or NSC668394. Animals were observed for primary tumor growth and metastasis formation. All animals were euthanized when primary tumor volume reached 2.0cm3, when animals had severe cachexia, or when animals showed signs of pulmonary insufficiency. Mice treated with NSC305787 and NSC668394 did not show any changes in the growth of their primary tumors and experienced similar survival times. However, our results suggest that NSC305787 inhibits osteosarcoma metastasis to lungs as confirmed by histopathological analysis. Therefore, when combined with adjuvant chemotherapy and surgical resection of the primary tumor, targeting ezrin with small molecules may yield a positive outcome and greater survival in a clinical setting. 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 4874. doi:1538-7445.AM2012-4874