A research group from The Netherlands Cancer Institute has discovered the mechanisms which limit access to the brain for two brain tumour drugs, inhibiting their chemotherapeutic effect.
They have established that the drugs (AZD1775 and PD0166285) have a high affinity for ATP-binding cassette (ABC) transporters based at the blood-brain barrier (BBB), which pump the drugs away from the brain, stopping it from reaching the tumour.
BBB: Easy As ABC?
The BBB separates systemic blood circulation from the highly sensitive central-nervous system, including the brain. This relies on a high level of selective permeability, with only certain elements of systemic circulation being allowed entry to the central nervous system.
In addition to a highly selective permeability, the BBB also has an array of transporters which pump potentially harmful foreign compounds and drugs away from the brain; ABC transporters are a major class of BBB transporters which have this important role.
Due to the highly invasive nature of brain tumours, they are inadvertently protected by the blood-brain barrier, and its ABC transporters. The research group found that AZD1775 is efficiently transported by two major ABC transporters, whereas PD0166285 is transported efficiently by one of these transporters.
Despite only being transported out of the brain by one of the transporters, this still equated to around a 5-fold reduction in PD0166285 from an in vivo brain-plasma ratio (in wild-type mice), with AZD1775 access to the brain being restricted 25-fold.
These drugs are designed to treat brain tumours by inhibiting Wee1, a kinase which facilitates a cell cycle checkpoint. By inhibiting Wee1 it is possible to stop cancer cells from replicating, where combination treatment with radiotherapy or chemotherapy can inflict the DNA-damage needed to kill the tumour cells.
This chemosensitizing effect has been utilised in previous clinical trials, with promising results for ovarian cancer.
In more recent discoveries the use of Wee1 inhibitors has been cited as a potential target for treating intracranial brain tumours, owing to the high expression of kinases like Wee1 in these tumours. This has led to the implementation of AZD1775 in multiple early phase clinical trials for brain tumours.
You Shall Not Pass: Drug-BBB Conundrum
The restricted access of Wee1 inhibitors to the brain exhibited in this research may indicate that the drug is not suited to treating brain tumours. However, this may be dependent on the results of the clinical trials.
This highlights a key issue in treating any neurological disease - how neurological diseases can be targeted when drugs are unable to reach highly protected brain tissue.
This is by no means an issue localised to brain tumour therapeutics, with a distinct lack of medications for a wide variety of neurological diseases. Neurodegenerative diseases have been plagued with issues of drug delivery and crossing of the BBB.
Alzheimer’s disease for instance, was first diagnosed back in 1906 and is now the largest killer in England and Wales, although there are still no effective therapeutics licensed to treat disease progression.
The blame for this can’t be solely placed on the selective permeability of the BBB, as Alzheimer’s disease is a complex disease with multiple genetic and environmental influences leading to onset and progression, but the ability to treat the components of the disease which we are aware of are made much more difficult when the blood-brain barrier is factored in.
Mark C. de Gooijer & Levi C. M. Buil & Jos H. Beijnen & Olaf van Tellingen ATP-binding cassette transporters limit the brain penetration of Wee1 inhibitors Investigational New Drugs. 17 November 2017. DOI: 10.1007/s10637-017-0539-8
Author: Geoffrey Potjewyd; Regenerative Medicine & Neuroscience PhD student at the University of Manchester. Top Image: Dr Khuloud T. Al-Jamal, Wellcome Images