Glioblastoma multiforme: novel therapeutic targets

ABSTRACT

Introduction

The increasingly detailed genetic characterization of glioblastoma (GBM) has failed to translate into meaningful breakthroughs in treatment. This is likely to be attributed to molecular heterogeneity of GBM. However, the understanding of the tumor microenvironment in GBM has become more refined and has revealed a wealth of therapeutic targets that may enable the disruption of angiogenesis or immunosuppression.

Areas covered

This review discusses the selective targeting of tumor-intrinsic pathways, therapies that target the GBM tumor microenvironment and relevant preclinical studies and their limitations. Relevant literature was derived from a PubMed search encompassing studies from 1989 to 2020.

Expert opinion

Despite appropriate target engagement, attempts to directly inhibit oncogenic pathways in GBM have yielded little success. This is likely attributed to the molecular heterogeneity of GBM and the presence of redundant signaling that allow for accumulation of adaptive mutations and development of drug resistance. Subsequently, there has been a shift toward therapies modulating the pro-angiogenic, immunosuppressive tumor microenvironment in GBM. The non-transformed cells in the microenvironment which includes endothelial cells, myeloid cells, and T cells, are presumably genetically stable, less susceptible to heterogeneity, and easier to target. This approach offers the highest potential for a therapeutic breakthrough in GBM.

KEYWORDS:

• Glioblastoma
• oncolytic virus
• personalized therapy
• signaling pathways
• immunotherapy
• tumor vaccines
• therapeutic targets
• oncogenic pathways
• tumor microenvironment
• tumor associated microglia and macrophages

Article Highlights

• GBM is a molecularly heterogeneous disease with signaling pathway alterations that vary at a single-cell level. This likely accounts for the clinical failures of therapeutic agents directed against single oncogenic pathways, such as peptide vaccine against EGFRvIII.

• The GBM tumor microenvironment is pro-angiogenic. While the role for the FDA approved VEGF inhibitor, bevacizumab, is still being defined, inhibition of integrin, Notch, and Wnt pathways are additionally being explored for anti-angiogenic effects in GBM.

• Immunosuppressive TAMs in GBM offer a wide range of therapeutic targets that affect their migration (e.g. LOX), polarization (e.g. STAT3), and phagocytic capacity. (e.g. CD47).

• Checkpoint inhibition in GBM has met with little success so far, but combination therapy with STING agonists, FGL2 inhibitors, or oncolytic viruses may boost T cell infiltration into GBM and render checkpoint inhibitors more effective.

• Ultimately, targeting the tumor microenvironment in GBM may offer the best chance for a therapeutic breakthrough.

This box summarizes key points contained in the article.

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

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

The work of the authors was funded by the U.S. Department of Health and Human Services, National Institutes of Health, National Institute of Neurological Disorders and Stroke, [NS094615]