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Proteasome inhibition for the treatment of glioblastoma


Roth, Patrick; Mason, Warren P; Richardson, Paul G; Weller, Michael (2020). Proteasome inhibition for the treatment of glioblastoma. Expert Opinion on Investigational Drugs, 29(10):1133-1141.

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.

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.

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Additional indexing

Item Type:Journal Article, refereed, further contribution
Communities & Collections:04 Faculty of Medicine > University Hospital Zurich > Clinic for Neurology
Dewey Decimal Classification:610 Medicine & health
Scopus Subject Areas:Life Sciences > Pharmacology
Health Sciences > Pharmacology (medical)
Language:English
Date:October 2020
Deposited On:23 Dec 2020 15:57
Last Modified:28 Feb 2021 08:02
Publisher:Informa Healthcare
ISSN:1354-3784
OA Status:Closed
Publisher DOI:https://doi.org/10.1080/13543784.2020.1803827
PubMed ID:32746640

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Content: Accepted Version
Filetype: PDF - Registered users only until 11 August 2021
Size: 238kB
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Embargo till: 2021-08-11