Around 200–300 children in Europe are diagnosed each year with diffuse midline glioma, a brain tumour that radiotherapy cannot cure because some cancer cells survive the treatment by communicating with nearby immune cells called microglia. This matters because radiotherapy is the only treatment that prolongs survival for these children, yet it typically buys less than a year. Decades of drug trials have failed to improve outcomes. The research team has discovered that microglia in the tumour slow down cancer cell division, and since radiotherapy kills rapidly dividing cells most effectively, this slowdown helps the cancer survive. What remains unknown is how this molecular conversation between microglia and cancer cells changes during radiotherapy, and which parts of that conversation are most vulnerable to disruption. If the project succeeds, it will identify specific drugs that block the survival signals between microglia and cancer cells, creating a new treatment strategy that combines a drug with radiotherapy. The team will then work with clinical researchers to design a trial testing this combination in patients. The computational tools developed will be released as open-source software, enabling other researchers to study cell-to-cell communication in different cancers.
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Context Diffuse midline glioma (DMG) is a highly lethal brain tumour that most often occurs in young children with around 200–300 cases diagnosed each year in Europe. The location of these tumours, in highly sensitive areas of the brain, prevents them from being surgically removed. Radiotherapy, using high energy x-rays to damage and kill the cancer cells, is currently the only treatment that is standardly offered to patients as it is the only treatment that has been shown to prolong survival. However, radiotherapy only partially shrinks the tumours or temporarily slows their growth and patients rapidly die of the disease, usually within a year of being diagnosed. Many clinical trials aiming to improve patient outcomes have tested different drugs, either alone or in combination with radiotherapy, but none has increased the survival of patients. There is therefore an urgent need for an alternative way of designing new treatment approaches. My team is researching how some of the cancer cells in DMG are able to survive radiotherapy. The tumours are made up of a variety of different cancer cells as well as normal brain cells, such as immune cells. We performed statistical analyses of data from tumour samples from patients to understand which of these types of cells were associated with worse response of the tumours to radiotherapy. We discovered that microglia, a type of immune cell in the brain, in the tumour are associated with the radiotherapy being less effective. We found that these microglia have a two-way molecular communication with cancer cells and may slow down the proliferation of the cancer cells. Radiotherapy mostly kills rapidly proliferating cells, so this slower proliferation may be what enables them to survive. The challenge that the project addresses We do not currently understand whether the communication between microglia and cancer cells changes in response to radiotherapy and how this communication, whether changing in response to radiotherapy or not, results in cancer cells surviving the treatment. Therefore, we do not know how to design new treatments that substantially improve survival through blocking the most vulnerable part of the molecular communication network between the cells or the effects of this communication on the behaviour of the cancer cells. Aims and objectives My proposal, combining experiments and computer modelling, aims to: (1) understand how the interacting cancer cells and microglia within the tumours are affected by radiotherapy and how these interactions lead to some of the cancer cells surviving radiotherapy; (2) find vulnerabilities in the molecular interactions between cancer cells and microglia and drugs that target those vulnerabilities to combine with radiotherapy and enhance its effectiveness. Potential applications and benefits My proposal will provide an understanding of how cancer cells are able to survive radiotherapy by communicating with microglia and a new treatment approach, combining a drug with radiotherapy to overcome this survival strategy. Following the completion of my project, I will work with other DMG researchers to confirm my team’s findings in other experimental systems and work with clinical paediatric neuro-oncology researchers to design a clinical trial to test the new drug-radiotherapy combination in DMG patients in the future. Also, we will release the computational methods used and developed by my team as open-source software, allowing other researchers to apply them to understand and target communication between cells in other contexts.
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