Changing paradigms for targeted therapies against diffuse infiltrative gliomas: tackling a moving target

ABSTRACT

Introduction: Gliomas are highly heterogeneous primary brain tumors which result in a disproportionately high degree of morbidity and mortality despite their locoregional occurrence. Advances in the understanding of the biological makeup of these malignancies have yielded a number of potential tumor-driving pathways which have been identified as rational targets for therapy. However, early trials of agents that target these pathways have uniformly failed to yield improvement in outcomes in patients with malignant gliomas.

Areas covered: This review provides an overview of the most common biological features of gliomas and the strategies to target the same; in addition, the current status of immunotherapy and biological therapies are outlined and the future directions to tackle the challenges of therapy for gliomas are examined.

Expert opinion: The limitations of current treatments are attributed to the inability of most of these agents to cross the blood–brain barrier and to the intrinsic heterogeneity of the tumors that result in treatment resistance. The recent emergence of immune-mediated and biological therapies and of agents that target metabolic pathways in gliomas have provided strategies that may overcome tumor heterogeneity and ongoing trials of such agents are anticipated to yield improved outcomes.

KEYWORDS:

• Gliomas
• targeted therapies
• tumor heterogeneity
• immunotherapy
• treatment resistance

Article highlights

• Despite our greater understanding of glioma pathogenesis and driving pathways, targeted therapy trials have not shown a survival benefit in glioma patients.

• Different targeted therapies against VEGF and EGFR have been studied including antibodies, tyrosine kinase inhibitors, and vaccines. However, none have shown significant overall survival in glioblastoma. Tumor heterogeneity plays a role in glioma resistant to targeted therapy.

• Viral-based therapies have shown encouraging results in early phase trials in glioblastoma and phase II and III trials of these agents are underway.

• Data from a single-agent or combination checkpoint blockade trial failed to show an overall survival benefit in recurrent glioblastoma.

• The neuro-oncology field eagerly anticipates the results of IDH1/2 inhibitor trials and looks forward to novel treatments targeting the metabolic pathways of gliomas.

Declaration of interest

VK Puduvalli has acted as site principal investigator for trials by DNAtrix, Novartis, Bexion, and Celldex; as a consultant for Orbus Therapeutics, SK Life Science and Threshold Pharma. The other authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or conflict with the subject matter or materials discussed in this manuscript apart from those disclosed.

Reviewer disclosures

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

Additional information

Funding

This paper was supported by NCI grant K24CA160777.