Faculty of Medical and Health Sciences


Overcoming the Blood Brain Barrier for the Treatment of Brain Cancers

Overcoming the blood brain barrier for the treatment of brain cancers

Patients with brain tumours, in general have a poor prognosis, as many of the current chemotherapies are unable to cross the blood-brain barrier (BBB). There is an urgent need to develop strategies that can overcome the BBB.  We have established an orthotopic intracranial murine model of glioma for investigating investigational anti-cancer agents for their ability to cross the BBB to target brain tumours.  When we tested DMXAA in this model, this stromal targeting agent was shown to be curative against the GL261 glioma when implanted subcutaneously, but had no activity against intracranial tumours. The poor anti-tumour effects against intracranial tumours correlated with low concentrations of DMXAA detected in brain tissue compared to plasma concentrations (1). On the other hand, novel, synthetic, epoxy-metabolites of omega-3-fatty acids were found in brain tissue at 100-fold higher concentrations than those on plasma. The pharmacokinetic data for these fatty acids indicate that they are able to cross the BBB and their potential for treating brain cancers is currently being investigated.  Another area of research in the laboratory is aimed at identifying  transporter proteins in the BBB that facilitate the transport of fatty acids into the brain, as well as efflux mechanisms that prevent agents such as DMXAA from accumulating in the brain.

References

Yung R, Seyfoddin V, Tijono S, McGregor A, Connor B, Ching L-M. Efficacy against subcutaneous or intracranial GL261 gliomas in relation to the plasma and brain pharmacokinetics of the vascular disrupting agent, 5,6-dimethylxanthenone-4-acetic acid (DMXAA) alone and in combination with lenalidonide. Cancer Chemother Pharmacol. 73, 639-649, 2014