Professor Susan Short and her team at the Leeds Centre for Translational Neuro-oncology are taking completely new approaches to glioma treatment. Ultimately, they want to develop this research for use in the clinic and use it to double survival.
The full programme of work brings together three projects.
The team are exploring the use of tumour-killing viruses, like one called Reovirus, that can be injected into the bloodstream and have been shown to reach the brain. Five different viruses are being investigated for their tumour-killing potential.
The team are testing these viruses in tumour cells in the lab. Their investigations are showing 1) how the virus replicates within the tumour cells, 2) the virus’s killing effects on the tumour cells and 3) whether the virus stimulates an immune response against the tumour. The most effective virus will be tested against tumours in pre-clinical models and assessed for: changes in an MRI scan; the impact on survival; immune response and how much virus reaches the tumour.
Many drugs are unable to reach a brain tumour as they cannot pass through the protective barrier that separates the brain from the bloodstream, known as the blood–brain barrier (BBB). However, blood cells are able to pass through the BBB. The team at Leeds are investigating whether immature blood cells taken from the bone marrow, called haematopoietic stem cells (HSCs), can be used as a method of delivering chemotherapy drugs to gliomas.
HSCs, that have been altered to fluoresce green, will be introduced into pre-clinical models. This means Professor Short’s team can visually track the movement of these blood cells through the body and confirm that they home in on the brain. The HSCs will then also be modified to contain and release drugs, which will prevent the tumour cells from thriving, and hopefully lead to tumour death.
As well as taking these new treatment approaches, Professor Short recognises that the quickest way to improve treatment success is to make current therapies more effective. Therefore, this third project aims to increase the effectiveness of conventional radiotherapy using two different approaches.
When tumour cells are damaged by radiotherapy, it’s thought that a process called ’Wnt signalling’ repairs the cells and aids tumour regrowth. By blocking Wnt signalling, the team are testing whether they can make radiotherapy more effective and prevent regrowth after treatment.
Small molecules called miRNA switch genes on and off, which in turn regulates cellular processes. This regulation is essential to maintain a balanced environment within the cell, and within the body. Professor Short is particularly interested in this, as certain cell processes can increase tumour growth or cause tumour death. By identifying miRNA mimics and blockers, tumour death can be started, and tumour growth can be stopped.
Delivery of these small molecules to the brain is an ongoing challenge due to the BBB, so the team is also looking at different delivery methods to get these molecules to the brain (including the potential of using viruses for delivery).
Gliomas remain difficult to treat for a number of reasons:
This research aims to overcome these difficulties, investigating novel approaches to glioma treatment with the hope they can be rapidly developed for use in the clinic, and can start saving lives today.
The therapies being investigated are aimed at both adults and children with gliomas. This is great news, as it means the potential impact this can have on our community reaches far and wide.
The laboratory testing for the Reovirus has been completed and has shown promising results. Separate to this grant, Reovirus is being tested in a human clinical trial, known as REOGLIO, which we co-fund with Cancer Research UK. The tests for another virus, HSV1716, have also shown promising results, confirming that the virus successfully stimulates an immune response when delivered into the bloodstream.
Laboratory experiments blocking Wnt signalling in human cells provided inconsistent results. Therefore, this area of the project was halted.
The team identified a miRNA mimic, but there was no effect on survival in their tests. They also saw no effect on survival when using the HSV1716 virus as a vehicle to carry the miRNA mimic to the brain.
The success of this project has led to a new, early phase clinical trial using the HSV1716 virus. We look forward to following this up in the future.
The team are now also exploring the interaction between the HSV1716 virus therapy and traditional cancer treatments (including radiation).
To see if experiments blocking Wnt signalling should continue, the team are screening human cells to eliminate any genetic differences and, hopefully, inconsistencies in results they see.
To increase the effectiveness of the miRNA mimic, the team are going to explore other methods of delivering the drug to the brain.
Research is the only way we will discover kinder, more effective treatments and, ultimately, stamp out brain tumours – for good! However, brain tumours are complex and research in to them takes a great deal of time and money.
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Although many new treatments, mainly new targeted drugs, have been tested in the last few years, we are still very short of effective treatments. In this project we want to test some completely new ways of treating these tumours.