Medulloblastoma: Therapy with bortezomib/tumor necrosis factor-related apoptosis-inducing ligand

Abstract

Today medulloblastoma as a typical tumor in children has only limited therapeutic options. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) has emerged as a promising anti-neoplastic cytokine with little side effects on normal cells. However, since primary cells from solid tumors are mostly TRAIL-resistant, combinatorial protocols have been intensively tested to restore TRAIL-sensitivity in these tumor cells. Especially “targeted therapies” like proteasome-, methyltransferase- or HDAC-inhibition have demonstrated synergistic effects with TRAIL in apoptosis induction in medulloblastoma cell lines. By directed reactivation of suppressed apoptotic pathways (e.g. caspase-8 silencing), substances like bortezomib, 5-aza-2'-deoxycytidine or valproic acid potentiate TRAIL-induced apoptosis in tumor cells with negligible side effects on normal cells. Revealing the precise molecular mechanisms of TRAIL sensitization by these novel drugs will help to more precisely design an effective TRAIL-based therapy for an individual tumor within an individual patient. With a huge amount of promising preclinical data, the clinical benefit of these combinatorial strategies for medulloblastoma treatment still needs to be demonstrated.