EXTH-14. INHIBITION OF THE ANGIOTENSIN II TYPE 2 RECEPTOR AT2R IS A NOVEL THERAPEUTIC STRATEGY FOR GLIOBLASTOMA

Abstract Glioblastoma (GBM) is a primary malignant brain tumor with poor clinical outcomes. Standard of care consists surgical debulking followed by radiation and temozolomide, but the invariably recurs, median survival only ~18 months. Repurposing drugs used for treatment other diseases promising avenue to identify novel treatments this highly aggressive form cancer. One such class compounds angiotensin II (AngII) receptor blockers, commonly control blood pressure. We show that ~80% human GBM express type 2 (AT2R). In presence AngII, inhibition AT2R using either PD123319 or EMA401 significantly inhibits proliferation. This effect was lost in cells CRISPR/Cas9 mediated knockdown AT2R. inhibited invasion, angiogenesis, reduced spheroid growth induced apoptosis through caspase 3/7 activation. Furthermore, changes number regulatory pathways including apoptosis, DNA replication focal adhesion. The crystal structure bound revealed be an active-like conformation helix-VIII blocking G protein β-arrestin recruitment. demonstrate architecture interaction differs drastically from complexes compounds. Conjugation angiopep-2 enhanced its barrier passage volume orthotopic xenograft model GBM. Targeting therapeutic strategy treat should explored patients.