ABSTRACT
Introduction
Glioblastoma multiforme (GBM) is the deadliest type of brain cancer with poor response to the available therapies, mainly due to intrinsic resistance mechanisms. Chemotherapy is based on alkylating agents, but DNA-repair mechanisms can revert this cytotoxic effect. O6-methylguanine-DNA methyltransferase (MGMT) protein is the primary mechanism for GBM resistance. Therefore, different strategies to suppress its activity have been explored. However, their clinical use has been hindered due to the high toxicity of MGMT inhibitors verified in clinical trials.
Areas covered
This review article aims to provide the current progress in the development of novel drug delivery systems (DDS) to overcome this resistance. Here, we also review the current knowledge on MGMT-mediated resistance and the clinical outcomes and potential risks of using MGMT inhibitors.
Expert opinion
To overcome therapeutic limitations, nano-based approaches have been proposed as a suitable solution to improve drug accumulation in the brain tumor tissue and decrease systemic toxicity. DDS to overcome MGMT-mediated resistance in GBM have been mostly developed to deliver MGMT inhibitors and for gene therapy to modulate MGMT gene expression.
Article highlights
MGMT-mediated resistance limits therapeutic success in GBM patients
Concomitant therapy of alkylating agents and MGMT inhibitors enhance sensitivity to treatment
MGMT inhibitors exacerbate the toxicity of alkylating agents in the healthy tissues
Brain tumor-targeting NPs can reduce systemic toxicity and enhance the therapeutic success
Further development is required to introduce DDS targeting MGMT-resistance to the clinical practice
Declaration of interest
The authors have no 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
A reviewer on this manuscript has disclosed receipt of research funding from NIH and is a co-owner for Accelerating Combination Therapies*. Ashvattha Therapeutics Inc. has also licensed one of her patents (*includes equity or options). Peer reviewers on this manuscript have no other relevant financial relationships or otherwise to disclose.