Targeting Axl: a potential therapy for glioblastoma

Abstract

Glioblastoma (GBM) is the most common and malignant form of adult brain cancers with a 5 year survival rate of less than 12%. One of the reasons for this poor survival is the highly infiltrative nature of GBM cells that results in tumour recurrence following initial therapy. Targeting GBM invasion is therefore a key to successful treatment for GBM patients. Targeted therapies such as the epidermal growth factor receptor (EGFR) inhibitor Erlotinib are currently under pre-clinical evaluation for treatment against GBM. One of the mechanisms of action for these types of therapies is to inhibit key signalling pathways that mediate the invasive phenotype of GBM. While the EGFR is commonly overexpressed in GBM and is therefore a potential target, both pre-clinical and clinical evidence suggests that EGFR inhibitors are ineffective. The Axl tyrosine kinase receptor is often over-expressed in brain cancer, and this expression is associated with a poorer prognosis. Like EGFR, Axl regulates cellular invasion and has the potential to mediate resistance to EGFR-targeted therapies. The small molecule Axl tyrosine kinase inhibitor BGB324 is currently under clinical evaluation against a number of cancer types and in collaboration with Professor James Lorens and his group at the University of Bergen, Norway, we are investigating its action as part of a larger study to assess Axl as a potential target for GBM therapy. The NZ brain cancer cell line panel, one of the largest collections of brain cancer cell lines in the southern hemisphere, was developed from a decade-long partnership between the Auckland Cancer Society Research Centre and the Department of Neurosurgery, Auckland Hospital. Early passaged cell lines were developed from patient samples under a 5% O2 atmosphere that mimics physiological levels in patients. We developed a 3-dimensional collagen invasion assay to investigate the anti-invasive effect of BGB324 on 10 NZ GBM cell lines. The results suggest that the Axl receptor could be a useful chemotherapeutic target for some GBM patients.