Emerging targeted therapies for glioma

ABSTRACT

Introduction: Gliomas are the most common malignant primary brain tumors in adults. Despite aggressive treatment with surgery, radiation and chemotherapy, these tumors are incurable and invariably recur. Molecular characterization of these tumors in recent years has advanced our understanding of gliomagenesis and offered an array of pathways that can be specifically targeted.

Areas covered: The most commonly dysregulated signaling pathways found in gliomas will be discussed, as well as the biologic importance of these disrupted pathways and how each may contribute to tumor development. Our knowledge regarding these pathways are most relevant to Grade IV glioma/glioblastoma, but we will also discuss genomic categorization of low grade glioma. Further, drugs targeting single pathways, which have undergone early phase clinical trials will be reviewed, followed by an in depth discussion of emerging treatments on the horizon, which will include inhibitors of Epidermal Growth Factor Receptor (EGFR) and receptor tyrosine kinases, Phosphoinositide-3-Kinase (PI3K), angiogenesis, cell cycle and mutant Isocitrate Dehydrogenase (IDH) mutations.

Expert opinion: Results from single agent targeted therapy trials have been modest. Lack of efficacy may stem from a combination of poor blood brain barrier penetration, the genetically heterogeneous make-up of the tumors and the emergence of resistance mechanisms. These factors can be overcome by rational drug design that capitalizes on ways to target critical pathways and limits upregulation of redundant pathways.

KEYWORDS:

• Glioblastoma
• low grade glioma
• signal transduction
• receptor tyrosine kinase
• Epidermal Growth Factor Receptor (EGFR)
• Phosphoinositide-3-Kinase (PI3K)
• mammalian Target of Rapamycin (mTOR)
• angiogenesis
• cyclin-dependent kinase
• isocitrate dehydrogenase (IDH)
• targeted therapy
• precision medicine

Acknowledgement

We wish to acknowledge the support of the John Fountas Brain Tumor Research Fund and K12 Paul Calabresi Clinical Oncology Award Training Program in Nervous System Tumors (K12CA090354).

Declaration of interest

PY Wen has received research support from Acerta, Agios, Angiochem, Exelixis, Genentech/Roche, GlaxoSmithKline, Karyopharm, Merck, Novartis, Sanofi-Aventis and Vascular Biogenics. 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 apart from those disclosed

Additional information

Funding

This paper was funded by the Dana-Farber Cancer Institute, the John Fountas Brain Tumor Research Fund, Massachusetts General Hospital and JJ Miller received research support from the Paul Calabresi Career Development Award for Clinical Oncology (K12CA090354).