Despite huge progress in the treatment of many cancers, the prognosis for those with brain cancer remains bleak. Even with the best available treatment, patients with the most aggressive brain tumours live for only 12-15 months.
Treatment for brain tumours often fails because cancer cells remain in the brain after surgery. These cells resist being killed by radiation and chemotherapy, and ultimately give rise to new tumours. In this project, Mr Ryan Mathew and Dr Heiko Wurdak brought together a team of neurosurgeons and biologists from across three universities to tackle this problem.
Mr Ryan Mathew and Mr Stuart Smith (University of Nottingham) are consultant neurosurgeons and brain cancer researchers who perform brain tumour surgeries weekly and have obtained PhDs in lab-based brain cancer science; Dr Heiko Wurdak (University of Leeds) and Dr Ruman Rahman (University of Nottingham) are brain cancer scientists with extensive experience studying the behaviour of cancer cells; Dr Peter O’Toole (University of York) is an expert in ‘cell mapping’ technology and Alison Ritchie (University of Nottingham) is an expert in developing animal systems for the study of human disease.
Glioblastoma is the most common primary brain cancer in adults, with around 2,500 cases diagnosed every year in the UK.
It is an aggressive, invasive tumour that grows and spreads quickly, and infiltrates the brain.
The current treatment strategy includes surgery to remove as much tumour as possible, followed by radiotherapy and chemotherapy to destroy remaining tumour. This prolongs survival but is not curative. Only a quarter of patients survive more than a year from diagnosis.
The need for better understanding and new treatments is urgent.
Read more: About brain tumours
One of the main barriers to successful treatment of brain cancer is that the tumours do not have a clean boundary; they grow into the surrounding healthy brain. This makes surgical removal extremely challenging and means that, whilst surgery is often effective at removing the majority of the brain cancer ‘bulk’, cancer cells are almost always left behind in a ‘margin zone’ that comprises both cancer cells and healthy brain tissue.
Unlike surgery for cancers in other parts of the body, brain surgeons cannot take out extra tissue to be sure of getting all the cancer cells - the risk of damaging vital brain tissue is too high. These remaining cells are therefore targeted with radiation and chemotherapy but, despite this, the tumours almost always regrow. However, even though the cells in the margin zone cause relapse, very little is known about the way in which these cells behave. Understanding the difference between the cells in the tumour ‘bulk’ and those in the margin zone is therefore crucial to finding new ways to prevent relapse.
In this project, the team recreated human brain cancer surgery in mice and rats, to enable the team to study the cancer cells in the margin zone; work on better ways to eliminate these cells; and test treatments that might be given after surgery.
One of the ways in which new treatments can be given after surgery is by using the cavity created by the removal of the tumour ‘bulk’ to deliver gels or pastes that can release drugs intended to prevent the return of the tumour. Experiments conducted by the team identified a drug that could be released over a three-week period from a paste that was suitable for testing within the cavity created in the animal model. These experiments showed increased survival of animals that received local therapeutic delivery of the paste after surgery when compared with control animals that received surgery alone.
In a second study, the team also established that physical devices can be implanted into the cavity after surgery. These devices can be used both for treating the residual cells left behind after surgery, and for monitoring the leftover cancer cells around the cavity. This proof-of-feasibility has contributed to the ongoing development of specialised, miniaturised brain-computer interface implants, which have proceeded to large animal studies and are on track for first-in-human trials.
The third objective of the grant was to investigate why brain cancers return after treatment; which of the body’s immune cells are involved; and why these immune cells are not effective in eliminating the cancerous cells. The team did this by comparing the brain tumour ‘bulk’ removed by surgery with the edge of the remaining tissue, and with the tumour when it returned. The results are still being analysed – but they already show exciting and significant changes over time in the area around the surgical cavity that might explain why the body’s natural defence system cannot target and eliminate the leftover cancer cells.
Animal models of brain cancer are a crucial resource in the study of brain tumours, to take forward our understanding of how tumours develop and grow in a living system, and how they respond to new treatments. However, new treatments developed in animal models often have poor translation to the clinic because they miss the critical tumour ‘debulking’ surgery step which neurosurgeons perform in human patients.
Mr Mathew and his team have now successfully re-created this ‘debulking’ surgery in both a mouse and a rat model, and have shown that these models can provide valuable insight into brain tumours and their potential treatment. These models can now be taken forward to further understand the brain cancer cells left behind after surgery, which are ultimately responsible for treatment resistance and tumour recurrence. This understanding and these models can also be used to trial new drugs and devices to tackle brain cancer.
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