Medulloblastoma is the most common type of malignant brain tumor in children. The disease can be treated effectively, but in a significant proportion of children the cancer keeps coming back. In addition, some children are so young at diagnosis that they cannot be treated with radiotherapy due to serious long-term side effects. The prognosis of children with this SHH form of medulloblastoma is not good: depending on other factors, up to half of patients die. New treatments are sorely needed.
A new study has started this month looking at the possibility of using the existing chemotherapy gemcitabine against this specific form of medulloblastoma. Previous research by Dennis Metselaar in the Hulleman group found that the SHH subgroup of ATRT, another type of brain tumor, is particularly sensitive to gemcitabine. The drug’s working mechanism has to do with the so-called SHH signal chain in cells, which has higher activity levels in SHH tumors.
Dr. Hans Meel is a trainee pediatrician and a postdoc in the Hulleman group. In the new pilot study, he will first examine whether 3D mini tumors from SHH medulloblastoma are just as sensitive to gemcitabine as SHH-ATRT. If this is confirmed, the next phase of the research will involve treating mice with SHH medulloblastoma with gemcitabine to study the drug’s therapeutic benefit.
‘The big advantage of gemcitabine is that its safety has already been proven in children,’ explains Meel. ‘Treatment protocols already exist for liver cancer, for example, and the drug has already been tested in children with other brain tumors, such as DIPG and glioblastoma. We are still at an early stage, but our hope and expectation is that gemcitabine will also work in the SHH subgroup of medulloblastoma.’
In the pilot study, Meel will analyze gene activity to study whether gemcitabine works in the same way in SHH medulloblastoma as was shown in previous research. Next, follow-up studies are planned to delve deeper into the biological effect and to investigate with which other therapies gemcitabine could best be combined.
SHH medulloblastoma is characterized by abnormal activity of the so-called ‘Sonic Hedgehog’ signaling pathway in the cell. This chain reaction allows tumor cells to divide indefinitely and makes them resistant to chemotherapy and radiation. Meel: ‘Gemcitabine works by rapidly breaking down a central protein in this signal chain, robbing tumor cells of these properties. Therefore, gemcitabine is a promising agent for SHH subgroups.’
Hans Meel's research into SHH medulloblastoma is funded by Koppie-Au, a charity that supports brain tumor research. The study started at the beginning of March, and the aim is to complete the pilot at the end of 2021 and then conduct a follow-up study. The research is carried out in collaboration with the research group of Marcel Kool and pediatric oncologist Sabine Plasschaert.