Proteasome inhibition for the treatment of glioblastoma

ABSTRACT

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.

KEYWORDS:

• Glioblastoma
• brain tumor
• neuro-oncology
• chemotherapy
• proteasome
• marizomib
• bortezomib

Article highlights

• The ubiquitin-proteasome pathway is a key regulator of many cellular processes

• Inhibition of the proteasome results in anti-proliferative and pro-apoptotic effects in glioma cells

• A clinical benefit derived from proteasome inhibitors has not yet been demonstrated in larger clinical trials for glioblastoma patients

• Marizomib is a novel, brain-penetrant pan-proteasome inhibitor which is being explored in clinical neuro-oncology

• Proteasome inhibition may be exploited in combination with other therapeutic strategies such as immunotherapy or molecular targeted agents to further enhance clinical benefit

This box summarizes key points contained in the article.

Declaration of interest

P Roth is the Study Chair for the EORTC 1709 trial and has received honoraria for lectures and advisory board participation from Bristol-Myers Squibb, Debiopharm, Medac, Merck, Novocure, QED and Roche and research support from MSD and Novocure. PG Richardson has been a clinical investigator on trials investigating proteasome inhibitors and has served on advisory committees for Takeda and BMS/Celgene and has also received research funding from Takeda and BMS/Celgene. M Weller has been a clinical investigator on trials investigating proteasome inhibitors and has received research grants from Abbvie, Adastra, Dracen, Merck, Sharp & Dohme (MSD), Merck (EMD) and Novocure, and honoraria for lectures or advisory board participation or consulting from Abbvie, Basilea, Bristol Meyer Squibb (BMS), Celgene, Medac, Merck, Sharp & Dohme (MSD), Merck (EMD), Nerviano Medical Sciences, Orbus, Philogen, Roche and Tocagen. WP Mason has been a clinical investigator on trials investigating proteasome inhibitors. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

One reviewer has received research support from BMS and has received Speaker’s bureau and Advisory Board fees from Novocure. Peer reviewers on this manuscript have no other relevant financial or other relationships to disclose

Additional information

Funding

This paper was not funded.