Proteasome inhibition for the treatment of glioblastoma.

INTRODUCTION: Glioblastoma is a primary brain tumor with a poor prognosis despite multimodal therapy including surgery, radiotherapy and alkylating chemotherapy. Novel therapeutic options are therefore urgently needed; however, there have been various drug failures in late-stage clinical development. The proteasome represents a key target for anti-cancer therapy as successfully shown in multiple myeloma and other hematologic malignancies. AREAS COVERED: This review article summarizes the preclinical and clinical development of proteasome inhibitors in the context of glioblastoma. EXPERT OPINION: Early clinical trials with bortezomib ended with disappointing results, possibly because this agent does not cross the blood-brain barrier. In contrast to bortezomib and other proteasome inhibitors, marizomib is a novel drug that displays strong inhibitory properties on all enzymatic subunits of the proteasome and, most importantly, crosses the blood-brain barrier, making it a potentially very active novel agent against intrinsic brain tumors. While preclinical studies have demonstrated significant anti-glioma activity, its clinical benefit has yet to be proven. Exploiting the biological effects of proteasome inhibitors in combination with other therapeutic strategies may represent a key next step in their clinical development.