490P - Inhibiting glioma cells' migration: Exploring Rho-GTPases as a potential therapeutic target

Background

Glioblastoma multiforme (GBM) is the most aggressive and incurable form of the central nervous system’ tumors. One of the characteristics hindering the efficacy of treatments is the diffuse infiltration of glioma cells into the surrounding parenchyma. Glioma stem cells (GSC) have been reported as the putative population responsible for glioma invasion and recurrences. The identification of new therapeutic targets blocking glioma cells migration is therefore of primary importance. Since many studies have focused on the role of small GTP-binding proteins of the Rho GTPases family in cancer cells motility, we here aimed to identify effective inhibitors of Rac1 and Cdc42, from in silico to in vitro study.

Methods

Docking and molecular dynamics simulations were used to identify and validate binding sites on target proteins. Virtual screening simulations, based on the known structure of targets, were applied to select possible inhibitors of Rho GTPases. Selected compounds were tested, on U87 MG glioblastoma cells, to exclude cytotoxic effects and to evaluate their ability to interfere with cell migration, in vitro. Finally, we tested the ability of the more effective compounds to inhibit the in vitro migration of 18 patients derived-GSC.

Results

Binding sites on Rac1 and Cdc42 GTPases were identified and validated, and a small number (21) of possible inhibitors were selected for in vitro studies. 3 compounds had shown a reduction of U87 cells migration greater than 50%. Interestingly, GSCs showed a different migration behaviour among patients and different sensibility to the tested compounds.

Conclusions

Three molecules, selected on the basis of in silico studies predicting their binding to Rho GTPases, were able to efficiently interfere with the migration capability of glioma cells in vitro.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

University of Udine.

Funding

Regione Autonoma Friuli Venezia Giulia - Italia, Ministero dell'Università e della Ricerca - Italia.

Disclosure

All authors have declared no conflicts of interest.