Proteasome inhibition for the treatment of glioblastoma

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.

This review article summarizes the preclinical and clinical development of proteasome inhibitors in the context of glioblastoma.

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.