CSIG-13. SYNERGISTIC EFFECTS OF HDAC INHIBITION AND HIPPO SIGNALING PATHWAY REGULATION IN GLIOBLASTOMA

Abstract Glioblastoma (GBM) is characterized by high morbidity and resistance to conventional therapies. Targeting epigenetic regulators and signaling pathways may offer novel therapeutic avenues. In this study, we evaluated the therapeutic impact of combining the HDAC inhibitor SAHA (suberoylanilide hydroxamic acid) with Verteporfin, a Hippo signaling pathway regulator, in patient-derived GBM tumor spheres (TS13-64 and TS15-88). We assessed cell viability, synergy scores, ATP activity, and protein expression through Western blot analysis. Gene expression changes were analyzed using microarray and RNA sequencing. Additionally, in vivo studies were conducted using bioluminescence imaging and survival analysis in luciferase-tagged TS13-64 orthotopic xenograft models. The combination of SAHA and Verteporfin significantly reduced cell viability and yielded high synergy scores, indicating an effective interaction between the two drugs. Microarray and real-time PCR analyses revealed decreased HDAC and YAP expression following treatment. We also observed reduced stemness and invasiveness of GBM tumor spheres, as evidenced by decreased neurosphere formation and altered protein expression profiles associated with these phenotypes. In vivo, the combined treatment led to a significant decrease in bioluminescence intensity, suggesting reduced tumor burden. Survival analysis showed a trend toward prolonged survival in treated animals. Our findings suggest that combined modulation of HDAC activity and Hippo pathway signaling represents a promising therapeutic strategy for GBM. This dual-targeted approach may overcome current treatment resistance and improve clinical outcomes in GBM patients.