Brain tumours are the second most common tumour in children (around 20% of all childhood cancers), and gliomas are the most common type. Gliomas appear in different ‘grades’ – low-grade, in which the tumour cells appear to divide more slowly, and high-grade, where the cells seem to divide more quickly when viewed under the microscope – making them more aggressive.
In adult high-grade glioma (aHGG), a drug called Temozolomide (TMZ) is the only one currently known to be effective, but attempts to use this to improve the outcome in the childhood version (paediatric high grade glioma (pHGG) have been unsuccessful, and it is currently incurable, so we urgently need new ways to treat it.
Dr Beth Coyle (pictured below) and her team are developing and studying a new type of TMZ which can be delivered directly to the tumour tissue in children, with the aim of creating a more effective new treatment.
Their research in test tubes appears promising, and this collaborative project between the Universities of Bristol, Nottingham and Lincoln aims to develop a treatment which is highly toxic to the tumour, whilst not being toxic to the surrounding brain tissue.
Convection-enhanced delivery of N3-propargyl, a novel analogue of temozolomide
Dr Beth Coyle
The University of Nottingham
16 October 2017
Improving treatments for children’s brain tumours relies on doctors and scientists developing a better understanding of why current treatments fail, or become less effective as tumours progress. In aHGG, the adult tumour, TMZ is the only drug currently known to be effective, and forms part of standard care along with radiotherapy and, sometimes, surgery.
But in children, it doesn’t work, and Dr Coyle and her team have been researching the reasons why. One reason may be that prolonged treatment with TMZ may actually cause the tumour to develop into a more aggressive type – so early treatment may not help.
This project is looking both at ways to make TMZ more effective and at better ways to deliver the drug directly to the brain tumour without damaging healthy brain tissue surrounding it.
One way may be to dissolve new drug versions in artificial cerebral spinal fluid (aCSF), but there are a number of different options and drug formulations which the team needs to explore in the lab before they can get close to clinical trials.
In this project, Dr Coyle and her team will be looking at these different options to find the best one to take forward.
We urgently need new and effective treatments for childhood brain tumours, including pHGG, which is an aggressive form of cancer. It is often not possible to remove these tumours through surgery, because of where they occur.
Even when surgery is feasible, additional treatment is needed, and surgeons often can’t remove all of the cancerous tissue without damaging the healthy cells around it.
This research will help us to match a new and potent drug to a delivery system which is safer for children and suitable and effective for treating pHGG. The team will be focusing on pHGG and DIPG, cancers where there is the most need for new and effective chemotherapy treatments.
By finding out more about what happens when we deliver drugs to tumours in different ways, Dr Coyle and her team aim to develop better ways of treating pHGG and DIPG, to save more children’s lives in the future, and give survivors a better quality of life.
Dr Beth Coyle leads a research group with the Children’s Brain Tumour Research Centre which is focused on understanding and circumventing drug resistance and migration/invasion of brain tumours. Professor Malcolm Stevens originally developed TMZ.
Dr Tracey Bradshaw has led the biology arm of drug discovery programmes and leads in vitro studies investigating anti-tumour activity. She has longstanding collaborations with Dr Lyudmila Turyanksa, a chemical physicist, and Dr Pavel Gershkovich, who has a wealth of experience in analysing of anticancer therapeutic agents.
Collaborations are also established with Professor Steven Gill and Dr Steven Lowis, who are currently involved in treating children in Bristol using CED. The system is unique, and no other group worldwide is able to administer drugs to the brain this way.
Other collaborators include Dr Ali Bienemann, a preclinical scientist, and Mr Will Singleton, a neurosurgeon. Nottingham has state-of-the-art preclinical nuclear imaging and radiochemistry facilities led by Dr Jeni Luckett (who is already collaborating with Dr Turyanksa on an NC3Rs funded project), which will be key for distribution studies.