PROMISING research, which has implications for the development of treatments for medulloblastoma, the most common brain tumour in children, has emerged from a recent mouse model study.
Approximately 60 cases of medulloblastoma are reported each year, with a large disparity in patient outcomes. In their study, the researchers found the cancer could present as one of four subtypes. Within these types, three respond poorly to chemotherapy, resulting in 4–7/10 children not surviving the disease. One subtype, WNT-medulloblastoma, responds remarkably well to chemotherapy as Prof Richard Gilbertson, Director, Cancer Research UK Cambridge Cancer Centre, University of Cambridge, Cambridge, UK, explained: “Although they have this horrible cancerous tumour, they all do incredibly well.” He continued by outlining the problem that defined this research. “What we do not understand is the biology behind why these children are cured; why is chemotherapy so much more effective in this subtype than others?”
Using immunohistochemistry, the team looked at tumour cells and their surroundings in all four subtypes and healthy samples in mice. Their findings showed that in the three subtypes with poor outcomes, and the blood–brain barriers was intact, whereas in the WNT subtype vessels were branched and ‘leaky’. This suggested that large molecules, like those in chemotherapy drugs, are able to enter the brain in the WNT subtype but not in any other subtype.
Intrigued by the differences between the WNT subtypes, the researchers looked at what molecules were produced by the tumours and their effect. They found that this subtype, unlike the others, released WIF-1 and DKK1-4, which are WNT7A antagonists. WNT7A is a molecule, which contributes to the function intact blood–brain barrier.
The question was then, is it possible to manipulate the other subtypes to be more susceptible to developing a ‘leaky’ barrier. The researchers modified the signalling to the blood–brain barrier in non-WNT subtype mice so that they now produced the same chemicals as the WNT tumours. This resulted in the mice becoming responsive to the chemotherapy agent vincristine. This suggests that the problem is not the drugs used but rather the cancer subtype and its effect on its cellular surroundings. These techniques cannot yet be used in humans, however it is an exciting step forwards. Prof Gilbertson concluded that “it is vital, fundamental research like this that lays the foundations for clinical trials that could improve treatments for patients in the future.”