Posted July 17, 2014
Aykut Üren, M.D., Georgetown University
Osteosarcoma (OS) can affect individuals of any age but is the most common bone tumor in children, with the highest incidence occurring in adolescents. The primary tumor can often be treated successfully with surgical removal; however, almost all patients have microscopic metastases at the time the primary tumor is removed. Currently, the long-term survival rate is approximately 60%. The death of patients with OS is rarely due to effects of the primary tumor but most often because of metastases, primarily in the lung, that can occur many years after the primary tumor is removed. Dr. Aykut Üren and his colleagues at Georgetown University are developing drugs toward the goal of preventing OS metastases.
The protein ezrin is elevated in metastatic OS cells and has been found to be necessary for the spread and survival of OS metastases. Dr. Üren reasoned that a drug that could block ezrin's function might prevent OS metastasis. He and his team mounted a campaign to find and test small drug molecules that would bind directly to ezrin to prevent its binding with other proteins. Screening of over 3,000 compounds identified a set of 65 that bound to ezrin with good affinity; functional testing led to the identification of two lead drug candidates, NSC668394 and NSC305787.
Dr. Üren and his group, with support from a Fiscal Year 2009 Investigator-Initiated Research Award, continued experiments testing analogs and derivatives of these "lead compounds" to identify compounds with improved ezrin-binding or metastasis-preventing potential. After creation and testing of more than forty analogs, Dr. Üren determined that the original parent compounds, NSC668394 and NSC305787, performed the best in preliminary testing. Dr Üren used a mouse model of sarcoma to test the ability of these lead compounds to inhibit metastasis. As expected, treatment with lead compounds did not inhibit growth of primary tumors; however, significant prevention of lung and liver metastasis was observed in mice with early onset tumors when treatment with NSC668394 and NSC305787 was started after diagnosis of the primary sarcoma. Importantly, no toxic effects of either compound were observed in the mice. Dr Üren notes that little is yet known about the absorption, metabolism, or excretion of the lead compounds and believes that the effectiveness of the compounds may be improved by a more effective dosing schedule that can be defined once more is known about the pharmacology of the compounds.
To further elucidate the role of ezrin in metastasis, Dr. Üren's group sought to identify proteins whose binding to ezrin is disrupted by NSC668394 or NSC305787. They demonstrated that polyadenylate-binding protein (PABP1), a regulator protein translation, is an ezrin binding partner whose interaction with ezrin is inhibited by the lead compounds. This supports the hypothesis that ezrin contributes to metastases by modulating the efficiency of protein synthesis in tumor cells.
Dr Üren's team has identified and validated two candidate compounds, NSC668394 and NSC305787, that could be developed into targeted therapies against the spread of OS metastases. Additionally, Dr. Üren's work toward understanding the mechanism by which ezrin mediates the metastasis of OS tumor cells may lead to the development of other novel strategies to prevent the formation of metastases.
Paige M, Kosturko G, Bulut G, et al. 2014. Design, synthesis and biological evaluation of ezrin inhibitors targeting metastatic osteosarcoma. Bioorg Med Chem 22(1):478-487.
Briggs JW, Ren L, Nguyen R, et al. 2012. The Ezrin Metastatic Phenotype Is Associated with the Initiation of Protein Translation. Neoplasia 14(4):297-310.
Bulut G, Hong SH, Chen K, et al. 2012. Small molecule inhibitors of ezrin inhibit the invasive phenotype of osteosarcoma cells. Oncogene 31(3):269-281.