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a Frontiers of Cancer Research Presentation!

Published Fri Jan 29th 2016

Thursday 04 Feb/16 at 3:00 pm in QCRI Conf Rms 100/01! Dr. Aykut Üren, Professor, Depts. of Oncology, Biochemistry, and Molecular & Cellular Biology, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center (Washington, DC). "Development of small molecule inhibitors of Ezrin as anti-metastatic agents". 

Pulmonary metastasis is the main cause of mortality in osteosarcoma. Cytoskeletal protein ezrin has emerged as a key regulator of OS metastasis to lungs. Ezrin functioning as a structural scaffold links the actin cytoskeleton to the plasma membrane proteins, and regulates cell motility, invasion and survival.  Ezrin overexpression is associated with poor survival in osteosarcoma in humans, dogs and mice. We used surface plasmon resonance technology (Biacore) to screen small molecule libraries for compounds directly binding to ezrin. Compounds that directly bind to ezrin protein were evaluated in secondary functional assays. We used electric impedance technology (xCELLigence) to evaluate cellular toxicity, chemotaxis and HUVEC monolayer invasion. Additional in vivo experiments including zebrafish development and allograft metastasis were used to validate in vitro findings. Top two lead compounds were further evaluated in a transgenic mouse model of osteosarcoma (p53 and Rb deletion from osterix promoter) for anti-metastatic efficacy and PK/PD profiles. NSC305787 inhibited metastasis of spontaneously formed osteosarcoma and showed a favorable PK profile compared to NSC668394. Investigation of molecular mechanism of action revealed that NSC305787 inhibits ezrin phosphorylation without affecting the kinase activity and prevent protein-protein interaction between ezrin and PABP1 (poly A binding protein 1). In summary, we discovered a novel small molecule that inhibits ezrin function in multiple in vitro and in vivo assays and prevents lung metastasis on osteosarcoma. Furthermore, molecular mechanisms of small molecule action suggest potential new functional interactions of ezrin with nuclear proteins.

Host: Dr. Bruce Elliott (bruce.elliottb@gmail.com)

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