Glioblastoma and the blood-brain barrier: Please do not neglect.
O. van Tellingen; M.C. de Gooijer; N.A. de Vries; F. Lin, E.C.M. Kemper; J.H. Beijnen; Netherlands Cancer Institute, Amsterdam, Netherlands
Glioblastoma (GBM) is a devastating disease and almost invariably lethal with a median overall survival of 15 months. Advanced knowledge in the molecular pathology underlying malignancies has offered new handles and better treatments for several cancer types but not in case of GBM. This grim outcome is at least partly due to the lack of successful drug delivery across the blood-brain barrier (BBB).
The importance of the BBB as a hurdle to effective therapies for GBM is not always well appreciated. The BBB is formed by the brain endothelial cells that are closely connected by tight junctions, lack fenestrae and demonstrate low endocytic capacity. At the molecular level the endothelial cells are equipped with a range of efflux transporters. However, the leakiness of blood vessels in GBM as assessed by contrast-enhanced MRI has led many to believe that the BBB is not so much an issue.
We will present preclinical data using orthotopic transplantation and transgenic GBM mouse models demonstrating the importance of the BBB. First, despite the leakiness of the tumor vessels, they still express efflux transporters that are functionally reducing the exposure of brain tumors to a range of (targeted) agents. Secondly, leakiness is heterogeneous and GBM includes areas with (almost) intact BBB. Taking this knowledge to MRI and PET data of patients reveals the same patterns.
Thus, the delivery of drugs for treatment of GBM requires special attention, especiall in this era of targeted therapies as many of these novel agents are excellent substrates for efflux transporters. If we continue to neglect the impact of the BBB, we will continue to see drug failing miserably.