Primary brain tumours (gliomas) in adults remain amongst the most challenging cancers to treat. Many patients only survive just over a year despite optimal treatment with surgery, radiotherapy and chemotherapy. We need to understand why these cancers can grow even after treatment designed to kill cancer cells, and to investigate new, more effective treatments.
We are starting to understand the biology of brain cancer better, but we still seem a long way from being able to cure our patients. Work in many labs around the world in recent years has started to suggest new treatments, but most of the work is based on laboratory results that do not provide enough information to support the design of new clinical studies to test new drugs or new combinations of drugs with, for example, radiotherapy. To add this critical missing information, we need to test new ways of treating glioma using our mouse models of the disease. If we can show promising effects, we will be able to translate these results into new clinical studies and ultimately new treatments for patients.
Plan of work and impact of our studies
We have worked with mouse models of glioma in Leeds for many years, but are still improving how we do this – especially how closely we mimic tumours we find in the clinic, and the treatment that patients receive. In some circumstances we need to set up new models using, for example, tumour tissue taken straight from patients, to ensure that we use the very best and most representative models. Using these tumour models, we then set out to treat them, just as we do our patients, using highly focused radiotherapy combined with drug treatment. We have excellent technology to image (using MRI and CT) and treat these tumours in mice. We will also then follow up what happens to the animals with tumours by monitoring the health of the animals, often also repeating imaging of the brain (usually using MRI).
In most experiments we will compare animals in different treatment groups, for example radiotherapy alone or radiotherapy with a new drug. Many of the new drugs that we are testing are designed to kill rapidly-growing tumour cells (known as stem cells) in the gliomas and to therefore improve the healthy survival of animals with tumours. We also need to measure the effect of these drugs and combinations on normal brain, since we need to avoid causing significant damage to surrounding normal brain tissue. We will do this by testing the effect of treatment on tumour and normal brain tissue in the same experiment, by including normal brain in the radiotherapy-targeted area, or in separate experiments where we specifically treat normal brain tissue with radiotherapy and additional drugs.
Animal welfare and the Three Rs
Throughout this work we will adhere to all relevant guidance to ensure animal welfare, particularly when administering new drugs to the mice. As well as restricting volume and doses in experiments where we do not know the ideal dose, we will use very small groups of animals (usually three) to assess the effects of slowly increasing the doses given. We are very familiar with expected side effects of most of the treatments we will use and will monitor treated animals very closely to avoid distress and suffering. We will also use anaesthesia and analgesia as appropriate to minimise suffering. Numbers of procedures and investigations are also strictly limited – both in terms of total number of interventions and how many can be undertaken over specific intervals.
We have used alternative, non-animal models, including spheroids (balls of tumour cells), to do preliminary assessment of effect of treatment with new drugs and radiotherapy for many years. We are also working with a consortium to investigate a “tumour on chip” model that would be a more advanced version of this and would allow efficient screening of drugs without use of animals.
All experiments are designed to use the smallest number of animals possible. Whenever we can, we use models in which the tumours grow very reliably and predictably to reduce the number that need to be included, with no addition for tumours that do not grow. We use the less reproducible models, usually those using patient-derived material, only for definitive experiments where we need to be able to demonstrate that we have used relevant, patient-derived material. We reduce variability in experimental outcome through use of our highly accurate radiotherapy delivery system alongside imaging equipment (MRI), to ensure we can visualise tumours directly.
We have significantly refined our radiotherapy facility to the extent that we can now target very specific volumes of tumour or normal tissue without including large volumes of irrelevant tissue when administering treatment. The use of non-invasive brain imaging significantly refines our experimental work, since this provides information on tumour volume directly and will allow us to reach treatment endpoints before animals suffer the effects of tumour growth.
Read a non-technical summary of improving treatments for brain tumours (PDF).
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