Epilepsy drug may inhibit development of brain tumour in infants

Medulloblastoma (MB) is the most common malignant pediatric brain tumour and arises in the developing hindbrain. Radiation is a standard treatment in medulloblastoma patients and modern radiation therapy has been used to cure many children with this, often aggressive, cancer. Although current therapeutic options have been successful in prolonging patients’ survival, survivors usually suffer from severe side effects, including cognitive impairment and endocrine deficiency.

An alternative and the perhaps better therapeutic option would be a more directed therapy. However, such therapy must be both more efficient and give fewer side effects than current treatments.

Medication against a certain type of epilepsy can be a new way to treat Medulloblastoma in infants. A specific mTOR inhibitor can cross the blood-brain barrier and both reach and attack the tumour where it is located. This is shown by IGP researchers, in collaboration with American and British colleagues, and the results are published in the scientific journal Cell Stem Cell.

Many infant brain tumours have acquired alterations in the cancer gene MYCN that promotes tumour growth and metastatic spread to the spinal cord, leading to very poor prognosis. In the present study, the researchers used unique stem cells from the brain and showed that MYCN could convert these cells into tumours. This indicates that these cells are the likely source of medulloblastoma in infants.

MYCN is promoted by a cell signalling programme called the Sonic Hedgehog pathway. This is involved in regulating normal brain development but is often activated in medulloblastoma. Several drugs directed against the Sonic Hedgehog pathway have been actively tested before but they are not successful in the treatment of young children with brain tumours due to other severe side effects affecting their bones.

“I first tested if inhibitors of the Sonic Hedgehog pathway could target these tumour cells but without success. The tumour cells instead activated the protein Oct4 and another programme called the mTOR pathway, which made the tumour more aggressive,” says Matko Čančer, a postdoctoral researcher at IGP, who performed the studies in the lab.

Matko Čančer then showed that both Oct4 and the mTOR pathway are indeed correlating with poor prognosis in infant medulloblastoma patients. When he tested drugs that could target this pathway, the brain tumours were quickly killed and the metastatic spread to the spinal cord was blocked.

“We found that one of the mTOR substances we used passed the blood-brain barrier between the blood and the brain tissue, which suggests that it will actually reach the tumour and attack it in the brain. This is, of course, necessary in order for the drug to work efficiently in the clinic,” says Fredrik Swartling, who has led the research study.

“We further realised that similar mTOR inhibitors are commonly used to treat a certain type of epilepsy – by inhibiting abnormal cell growth in the brain – in children with the inherited disease tuberous sclerosis complex (TSC), and that these drugs have fewer side effects than the Sonic Hedgehog inhibitors tested. These are very promising findings and if this kind of precision medicine can work on young children with medulloblastoma, where standard treatment is not working, it would, of course, be fantastic,” says Fredrik Swartling.