Radiotherapy is an essential and effective treatment for many brain tumours, including glioblastoma, 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 reducing its beneficial effects.
This project set out to understand whether a new drug, AZD1390, could help protect the healthy brain from the damaging effects of radiotherapy. AZD1390 blocks a molecule that plays a key role in how cells respond to radiation, and AZD1390 is already being tested in patients to see whether it can make radiotherapy more effective against brain tumours. However, the effects of AZD1390 on healthy brain tissue are not known.
Professors Anthony Chalmers and Kaye Williams and their teams therefore undertook a series of experiments to determine whether – and how – AZD1390 modifies the effects of radiotherapy on the healthy brain.
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.
Read more: About brain tumours
Radiotherapy is a vital tool in the treatment of brain tumours. However, whilst it can be an effective treatment, it can also damage the healthy brain, so 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.
Prof Williams’ research showed that treating mice with radiotherapy caused a progressive deterioration in their neurological function over a six-month period. However, treating mice with AZD1390 for one week around the same time as radiotherapy significantly reduced these effects. In experiments aimed at understanding what causes these protective effects, Prof Chalmers and his team observed that AZD1390 suppresses the ability of radiotherapy to cause inflammation in the brain. These results suggest that adding AZD1390 to brain radiotherapy for patients with brain tumours might protect the healthy brain from the side effects of radiotherapy. This possibility is now being tested in clinical trials.
The use of mice was essential in this research. This aspect of the work was carefully reviewed and is subject to tight regulation by the Home Office. The team took the utmost care that the mice did not experience pain or discomfort, and their procedures were continuously monitored.
Read our policy on the use of animals in medical research
Because AZD1390 is already being tested in patients with glioblastoma, we urgently need to know how it affects the healthy brain. Specifically, whether it might cause damage or, conversely, have a protective effect.
This project’s novel observation that AZD1390 protects the healthy mouse brain from the adverse neurocognitive effects of radiation is therefore of direct clinical relevance. In fact, data obtained in this project have already influenced AstraZeneca to obtain similar data on neurocognitive outcomes from patients participating in an ongoing clinical trial that is testing AZD1390 in combination with brain irradiation in patients with glioblastoma.
The results from Prof Chalmers’ and Prof Williams’ project are highly likely to inform the design and delivery of future clinical trials of this kind, and the observation that AZD1390 modulates the effect of radiation has also driven the development of further preclinical studies comparing healthy brain tissue and brain tumours.
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