Radiotherapy is an effective treatment for many brain tumours but it can also damage the healthy brain. Many patients who receive radiotherapy for their brain tumour subsequently experience problems with memory, concentration and personality change. There is an urgent need to find drugs that can reduce the side-effects of radiotherapy without interfering with its beneficial effects.
This project focuses on a drug called AZD1390, which is currently being trialled in combination with radiotherapy to see if it can help patients with glioblastoma live longer. The effect of this combination on the healthy brain is not known and, while there is a possibility that it could make the side-effects of radiotherapy worse, some recent experiments have suggested that AZD1390 might actually reduce the side effects of brain radiotherapy.
A team led by Professor Anthony Chalmers (Glasgow) and Professor Kaye Williams (Manchester) will carry out a series of experiments to determine whether AZ1390 modifies the effects of radiotherapy on the healthy brain. The results will feed directly into the clinical trial, to guide assessment of neurological outcomes in patients.
Following rigorous assessment as part of our competitive grant round, this project was recommended for its strong potential to impact on the treatment of brain tumour patients. The collaborative project team is well-placed to succeed in the delivery of this exciting project.
Glioblastoma is the most common and most deadly primary brain cancer in adults. Around 2,500 new cases are diagnosed every year in the UK.
Glioblastoma is a grade four tumour, meaning that it grows and spreads quickly. It infiltrates the brain, wrapping finger-like tentacles around vital brain structures, making complete surgical removal impossible.
One of the mainstays of current treatment is radiotherapy, which follows surgery in a bid to destroy any remaining tumour cells. This is augmented by chemotherapy. All of this prolongs survival but is not curative. Only a quarter of patients survive more than a year from diagnosis. The need for new treatments is urgent.
Radiotherapy is a vital tool in the treatment of brain tumours. But, whilst it can be an effective treatment, it can also damage the healthy brain and there is an urgent need to find drugs that can reduce its side-effects without interfering with its beneficial effects.
We know that radiotherapy damages the normal brain by causing inflammation that continues even after the radiotherapy has finished. This inflammation causes irreversible damage to cells and structures within the brain, and eventually leads to problems with memory, concentration and personality change.
A family of cells within the brain called microglia are thought to be responsible for the inflammation; they are activated by radiotherapy and then travel around the brain, irritating other cells and damaging important brain structures.
Some previous research has suggested that a molecule called ATM might be involved in the process by which radiotherapy activates microglia. The team has done some small-scale experiments that support this idea. They were surprised to see that a drug called AZD1390, known to inhibit ATM, caused a big drop in the number of microglia after radiotherapy. They saw this reduction within 24 hours of treatment and it was still present nearly two months later. They now need to do some larger experiments to confirm these findings, work out why it is happening, and see whether AZD1390 can really protect the brain from the damaging effects of radiotherapy.
Professor Chalmers explains their approach:
We are going to ask these research questions in three different ways.
Firstly, we will use well-known tests of mouse behaviour to see if AZD1390 can reduce the severity of the side-effects of radiotherapy. Our previous experiments have shown that radiotherapy changes the behaviour of mice, so we are confident we will be able to see a difference if the AZD1390 is effective.
Next, we will use MRI brain scans to measure changes in the structure of mouse brains after radiotherapy, and see if the AZD1390 can reduce or prevent these changes. These MRI scans are also used to monitor patients with brain tumours, so the results will be very informative.
Finally, we will take brain tissue samples from mice treated with radiotherapy and AZD1390 and look at the number and shape of the microglia and other important cells so we can understand how the drug is having its effects. We will look at many different molecules on several different cell types in order to get the most information possible from these experiments. At the end of the study we will put all of this information together in order to get the complete picture.
The use of mice is essential in this research. This aspect of the work was carefully reviewed, and is subject to tight regulation by the Home Office. The team will take the utmost care that mice don’t experience pain or discomfort, and their procedures will be continuously monitored.
Because AZD1390 is already being tested in patients with glioblastoma, we urgently need to know how it affects the healthy brain – whether it might cause damage or actually have a protective effect.
As the first study of AZD1390 and radiotherapy on the healthy brain, this study will generate important new information with rapid clinical impact. Evidence from the project will support incorporation of new tools to measure neurological outcomes in those patients taking part in the clinical trial, and will strengthen the case for further development of the radiotherapy-AZD1390 combination.
This is a collaborative project between the Universities of Glasgow and Manchester, jointly led by Professor Anthony Chalmers in Glasgow and Professor Kaye Williams in Manchester.
Their team includes experts in neuroscience, psychology, psychiatry, brain tumours, MRI and radiotherapy. Professor Chalmers is an oncologist who treats patients with brain tumours. He runs several clinical trials testing radiotherapy-drug combinations in patients with glioblastoma and is closely involved in the clinical trial of AZD1390.
Professor Williams is in charge of radiotherapy-drug combination research at the University of Manchester, and also oversees all the laboratory projects involving MRI scanning. She has many years of experience in testing new radiotherapy-drug combinations in mice and several of her projects have successfully progressed from the laboratory to patients.
On all topics, models, methods and techniques, the applicants have the necessary expertise, resources and support to lead this research project. The applicants' track records fit perfectly with the topic. The collaborative nature of the project is clear, with separate and common work packages depending on everyone's experience and expertise. External reviewer.
Brain tumours are one of our current research priorities, reflecting the large unmet need in this area. Our aim is to fund research to advance understanding of the causes and underlying mechanisms of brain tumours, and help us to diagnose and treat them more effectively.
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