Dual inhibitor of PI3K/mTORC1/2, NVP-BEZ235, as a therapeutic strategy in in vitro and in vivo models with alterations of molecules involved in epithelial-mesenchymal transition of vulvar carcinoma

• Grant number: 14/03159-3
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• Start date: October 01, 2014
• End date: September 30, 2016
• Field of knowledge: Biological Sciences - Biology
• Agreement: Coordination of Improvement of Higher Education Personnel (CAPES)
• Principal Investigator: Rafael Malagoli Rocha
• Grantee: Iara Sant Ana Rodrigues
• Host Institution: A C Camargo Cancer Center. Fundação Antonio Prudente (FAP). São Paulo , SP, Brazil

Abstract

Vulvar squamous cell carcinoma is fourth most common type of gynecological cancer and usually is diagnosed in a stage still amenable to potentially curative treatments, including surgery and/or radiation therapy with or without chemotherapy. However, several patients present metastatic diseaseat diagnosis, among those, 30-50% will relapse and did not respond effectively to treatment. EMT has relevant roles during cancer progression, as proposed by several authors. It has been suggested that cancer cells, derived from normal epithelial cells that have suffered a given set of genetic/epigenetic alterations, upon certain chemical cues from the microenvironment, could undergo EMT thus gaining mobility and detaching from the primary tumor. In addition, these now invasive cancer cells could then intravasate to the blood stream and reach a secondary site in the organism. The reversible nature of EMT would at this point be activated: cancer cells at the secondary site could then undergo MET, regaining enough adhesion thus forming secondary tumors. Recent evidence has suggested that processes of the EMT may play a role in the development of chemoresistance, principally by upregulation of drug transporters, cell cycle and apoptosis genes. In addition to the EMT process is regulated by pathwaysthat is required to maintaintumor cells, such as via PI3K/mTOR. NVP-BEZ235, a dual inhibitor of PI3K and mTORC1 / 2, has been shown to be a promising drug in the treatment resistance. The effects of this dual PI3K/mTOR inhibitor have been attributed to the induction of cell cycle arrest, apoptosis, to its antiangiogenic properties and reduction of TEM. Therefore, the purpose and importance of our work is studying the effect of compound NVP-BEZ235 on the mechanisms of invasion, migration and cell proliferation in vitro models with alterations in molecules involved in the process EMT its application in vivo model of vulvar carcinoma, to determine possible less invasive therapies for these tumors. (AU)