Erlotinib: early clinical development in brain cancer

Glioblastoma (GBM) is the most common brain cancer in adults. It is also, unfortunately, the most aggressive type and the least responsive to therapy. Overexpression of EGFR and/or EGFRvIII is frequently found in GBM and is frequently associated with the more malignant phenotype of the disease and a poor clinical outcome. EGFR-targeted therapy represents a promising anti-GBM therapy. Two EGFR kinase inhibitors, gefitinib and erlotinib have been tested in clinical trials for malignant gliomas. However, the clinical efficacy of EGFR-targeted therapy has been only modest in GBM patients.

The authors provide an evaluation of erlotinib as a potential therapy for GBM. The authors highlight experiences drawn from clinical trials and discuss the challenges, which include the insufficient penetration through the blood-brain barrier (BBB) and chemoresistance.

Malignant brain tumours have a very complex signalling network that is not only driven by EGFR. This complexity dictates tumour sensitivity to EGFR-targeted therapies. Alternative kinase signalling pathways may be involved in parallel with the inhibited target, so that a single target's inactivation is not sufficient to block downstream oncogenic signalling. The use of nanocarriers offers many opportunities, such as the release of the drug to specific cells or tissues, together with the ability to overcome different biological barriers, like the BBB.