More than 400 children are diagnosed with a brain tumour every year in the UK.
Advances in treatment and care mean that around 80% of these children survive. Some pay a heavy price, however, due to the harm caused by the intensive treatments.
In this project, Dr Dan Williamson and Dr Debbie Hicks set out to map the brain’s response to radiotherapy, describing the individual cell types and brain structures that are most sensitive to injury. This will drive the development of new drugs to reduce or prevent cognitive problems in childhood cancer survivors.
Following rigorous assessment as part of our competitive grant round, this project was recommended for its strong potential to advance knowledge in this area of great clinical importance.
In many brain and non-brain cancers, the whole brain is treated with radiotherapy, either to treat the tumour or to reduce the risk of recurrence. This practice has helped to drive up the survival rate for children with brain tumours, but it is not without cost. Healthy brain tissue is exposed to the toxic effects of radiation, and damage is caused to normal cells and the genetic material within them.
In children, whose brains are undergoing rapid and defining development, this is particularly problematic and can result in serious cognitive issues. Childhood brain tumour survivors who have had radiotherapy to the whole brain show more problems with cognition than siblings, peers, and other cancer survivors who have not had radiotherapy to the developing brain.
Childhood brain tumour survivors have been shown to struggle at school, have fewer friends, and be more frequently under-employed. Ultimately this leads to a lower quality of life. Survivors of high-risk brain tumours such as medulloblastoma, the most common malignant brain tumour in childhood, are the worst-affected since they often receive very high-dose radiotherapy to the brain.
The biological mechanisms of radiation-induced injury, and how they correspond to cognitive decline, are not completely understood. Experiments, typically in animal models, have found that inflammation is part of the brain’s ‘injury response’ to radiation. Furthermore, the normal balance of the distinct cell types of the brain is disrupted following radiation exposure.
Previous work relied on experimenting on chunks of brain tissue containing a mixture of cells. The processing of this ‘bulk tissue’ yields what is akin to a mixed fruit smoothie - the different components are blended together, and the data cannot be disentangled to understand the specific contribution of different cell types.
The team will use new methodology to understand the biological response to radiotherapy with far greater precision. This so-called ‘single-cell RNA sequencing’ is a way of analysing gene expression in individual cells, rather than bulk tissue.
This technology has been used before, to create ‘atlases’ of the whole mouse brain, advancing understanding of region-specific brain biology. The team will focus on four areas of the brain that are important for cognitive function, describing their specific biological response and identifying the individual cell types and brain structures most sensitive to injury by radiotherapy.
They will use their atlas to identify unique features of normal brain tissue that has been exposed to radiotherapy.
The increasing survival from childhood brain tumours is cause for celebration, but the use of increasingly intensive treatments comes at a cost. Children exposed to toxic high-dose radiation suffer the consequences of this for the rest of their lives.
This important new project will help us understand how radiotherapy affects the different cells of the brain, and thus how we might mitigate these effects.
There are already some candidate drugs that are thought to prevent or reduce radiotherapy-induced cognitive decline, but these have not been sufficiently tested to be used in humans routinely. This new work will provide a biological rationale for choosing the best drugs, and will drive the development of new drugs to prevent or reduce cognitive problems in cancer survivors.
The team will make their ‘atlas’ publicly available in order to drive the next wave of innovation and discovery. It can also be applied to help understand traumatic brain injury, stroke and other brain injuries.
This project brings together a team of experts well-placed to successfully deliver this ambitious research.
Adding to Dr Williamson's expertise in childhood cancer genomics and bioinformatics and Dr Hicks' expertise in childhood brain tumour late-effects, the team also includes Professor Susan Short, bringing expertise in mouse radiotherapy; Professor Steve Clifford, an expert in translation of findings and development of new therapies; and Dr Sasha Gartside, who brings expertise in the structure and function of the mouse brain.
The team is embedded in the leading international research networks required for the application of their findings toward patient benefit.
Find out about our other research in this area:
