Androgen receptor antagonists- a potential treatment of GBM

Background: Glioblastoma is the most aggressive type of Brain tumor. We have previously demonstrated that androgen receptor (AR) is induced in 56% of the glioblastomas. AR antagonists, bicalutamide and enzalutamide as well as silencing of AR expression by siRNA induced concentration-dependent death in three glioblastoma cell lines and in glioma initiating-cell-lines. Methods and results: Clinical PET-CT scan using radioactive 16-beta-fluoro-5-alpha-dihydrotestosterone (F-FDHT), in patients with glioblastoma, validated our results and demonstrated that the overexpression of AR in GBM can be detected in patients at real time. Immuno- staining with anti-AR antibody showed nuclear translocation of AR in cell line over-expressing EGFR. Furthermore, inhibition of EGFR activity with Afatinib, reduced the phosphorylation of AR on serin-213. Combination therapy with EGFR inhibitor and AR blockers in GBM cell lines yielded improved efficacy. AR antagonist given orally to nude mice bearing subcutaneous xenografts resulted in a 72% reduction in tumor volume (p=0.0027) and increased significantly (p=0.0073) the lifespan of mice implanted intracranial with human GBM compared with mice treated with vehicle. Discussion: This study have indicated by several methods including PET-CT that AR is overexpressed in 50% of GBMs, and in list partly, is constitutively activated on serine 213 through EGFR signaling-pathway. Animal models of human GBM indicated that treatment with AR-antagonist reduced significantly the tumor volume and prolonged the life span of mice implanted intracranial with human GBM. We hope that in the near future this research will be use as a new approach of glioblastoma treatment in molecularly selected patients