ANGI-15COMBINED TARGETING OF NOTCH AND EGFR DISPLAY ADDITIVE INHIBITORY EFFECTS ON ANGIOGENESIS AND SURVIVAL IN GLIOBLASTOMA

Abstract

Glioblastoma (GBM) is a devastating tumor in adults characterized by extensive vascularization and poor survival. New treatment approaches include the targeting of angiogenesis with the hope of improving the outcome of GBM patients. In GBM, the EGFR receptor is often overexpressed or mutated and its activation was found to correlate with poor prognosis. Notch signaling is known for its role in angiogenesis during foetal development and in other cancers, but the importance of Notch signaling in GBM angiogenesis is still under investigation. GBMs often display dysregulation of the EGFR and Notch pathways and the putative crosstalk between these two pathways in regards to angiogenesis underlines their importance in gliomagenesis and therapeutic resistance. In this study, we aimed at elucidating the effect of combined targeting of both, the Notch and the EGFR signalling and its effect on angiogenesis and GBM tumor growth. In vitro experiments were performed using two patient-derived GBM cell cultures, both expressing EGFR and Notch. We demonstrated that a combined inhibition of Notch (γ-secretase inhibitor; DAPT) and EGFR (Iressa) downregulated expression of pro-survival genes (Akt and ERK), reduced expression and secretion of the angiogenic cytokine - VEGF; and displayed additive inhibition of cell viability assessed by MTT assay. Further, the abrogation of EGFR/Notch signaling in GBM cells reduced the degree of angiogenesis. Finally, DAPT and Iressa single-therapy reduced tumor-growth in vivo, however no significant benefit could be found upon combinational therapy. The present study implies that EGFR- and Notch signaling are important for GBM tumorigenesis and angiogenesis.