Modl-11. exploring the therapeutic potential of yap-tead inhibitors for targeting gbm cell migration at the infiltrative margin

Abstract Glioblastoma (GBM) is an aggressive brain tumor with a median overall survival of only 12-15 months. Despite remarkable cellular and molecular heterogeneity, all GBM subtypes exhibit an infiltrating growth pattern which leads to incomplete surgical resection and inevitable recurrence, representing a major obstacle for effective treatment and an unmet need for therapy. Our research project aims to investigate the efficacy of YAP-TEAD inhibitors, including Verteporfin (VP), on migratory properties of GBM cells at the interface between the tumor core and the infiltrative tumor margin. Recently, several groups have implicated Hippo pathway YAP-TEAD activation in GBM growth and mesenchymal transition, and our laboratory demonstrated anti-migration and anti-invasion efficacy of the YAP-TEAD inhibitor VP across GBM subtypes, in patient-derived cell and xenograft (PDX) mouse models. Here we set to develop an ex vivo model for high-throughput testing of various YAP-TEAD inhibitors using organotypic slice cultures obtained from PDX and primary glioblastoma resection specimens, focusing on tumor areas around the infiltrative margin. Tumor cells within 250µ-thick organotypic slices were infected with GFP labeled retrovirus and subjected to confocal time-lapse imaging 72-96 hours later. Slices were treated first with vehicle (DMSO) for 4 hours, and subsequently with the YAP-TEAD inhibitor VP for 4 hours. To assess drug impact on tumor cell migration, we gathered imaging data on migration properties such as speed and directionality. Analysis of a PDX model generated from a de-novo GBM surgical resection (G-17969) revealed significantly decreased distance traveled in GFP+ cells treated with VP, compared to DMSO (p-value = 0.0002, n=50 cells). These pilot results corroborate other studies demonstrating anti-invasion properties of VP, contributing towards our goal of establishing a preclinical pipeline for rapid, high-throughput screening of anti-invasion drug inhibitors ex vivo. Key words: Glioblastoma, cell migration, YAP-TEAD inhibitors, time-lapse imaging