Low-grade glioma is a rare brain tumour that predominantly affects young adults. There is no cure and all patients ultimately progress to high-grade glioma, at which their prognosis is around two years.
In this project, neurosurgeon Richard Mair has developed several novel models to investigate potential therapeutic opportunities to prevent low-grade to high-grade progression and therefore improve prognosis in this young patient group.
Low-grade glioma (LGG) is a rare brain cancer that predominantly affects young adults. There is no cure. Current treatment consists of surgery for diagnosis and to ‘debulk’ the tumour. This may be followed by radiotherapy, chemotherapy, a combination of the two and a prolonged surveillance period using MRI.
Despite the prolonged period of surveillance, which aims to detect tumour progression, there are no treatments that can completely halt this progression when it occurs. All patients with LGG will ultimately progress into high-grade glioma (HGG) at which point their prognosis is around two years.
Mr Mair proposes that the prolonged surveillance period in people with LGG is a perfect time during which to intervene. He believes that patient prognosis could be extended significantly by intervening whilst the cancer remains low-grade, rather than waiting for it to progress.
Read more: about brain tumours
LGG is commonly associated with a mutation to a gene called IDH within a patient’s brain cells. This mutation affects the way that a cancer cell makes energy (its metabolism). We know that this altered metabolism causes many changes to the way that genes are controlled within the tumour cells. We also know that these cancers become starved of oxygen as they grow. However, investigation into the cause, growth and response to treatment of these tumours has been limited by a lack of biologically accurate models that correctly reproduce the characteristics of these slow growing tumours.
In this project, Mr Mair and his colleagues have characterised a novel animal model of IDH mutant astrocytoma (a type of brain tumour) that faithfully reproduces the molecular underpinnings of this disease. Moreover, they have used novel cell culture techniques to derive additional models from patient material donated during surgery. By using these model systems, the team have further developed a method to explore how interactions between tumour cells and those of the immune system might regulate or promote tumour behaviour. Finally, the team used their experience of tumours grown in low oxygen environments – similar to those identified within patient tumours – to show that certain molecular characteristics of brain tumours are enriched in these circumstances.
The ability of cells to amplify abnormal signals has been demonstrated to occur via several mechanisms within the cell. Direct amplification of a signal that, e.g., tells the cell to grow and proliferate, has been implicated as a method by which cells might escape therapies targeted to inhibit those specific signals. The research undertaken in this project has demonstrated how this signal responds to the environment within a tumour (a lack of oxygen) and that this low oxygen environment further amplifies the signal, making these cells even harder to treat with targeted therapies.
This understanding of amplification, together with the models that Mr Mair has generated, can now be taken forward to explore therapeutic opportunities that try to inhibit this amplification itself.
Mr Mair and his colleagues have characterised several novel systems for the interrogation of IDH mutant glioma both in vitro and in vivo. In so doing, this project represents a key step on the pathway towards the identification and development of drugs that could block the progression from low-grade to high-grade glioma.
Despite the team’s access to human brain tumour samples, it was necessary to use animals (mice) in this research. The brain environment in which the transformation from LGG to HGG occurs is too complex to model outside of the living brain, and the changes that occur over time cannot be reproduced from static analysis of human samples. Therefore, it is necessary to use model systems that better represent the complex, dynamic environment of LGG transformation.
The team performed careful calculations, using their extensive experience in developing this technique, to minimise the number of animals required.
The use of animals is specifically addressed as part of our review process, to make sure that the use of animals is necessary, relevant and well-designed. All animal research carried out in the UK is tightly regulated by the Home Office and we require copies of the relevant licences before work can get underway.
Find out about our other research in this area:
