Imperial College London
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Imperial College has established a Centre of Excellence that combines all of the elements necessary for a successful and sustainable brain tumour research programme.
The researchers focus on the process of translational research providing a platform for greater understanding of brain tumour biology, improvements in the patient pathway and new diagnostic and monitoring technology. In combination with safer and more effective treatment options, this will lead to increased survival.
This requires an integrated approach between laboratory and clinical research. This is essential as one drives the other -- they are heavily interdependent. Clinical data collection and surgery provides the tissue substrate for the laboratory to drive new approaches, techniques and treatments. In turn, these then need to be validated again clinically. This is the basis for good translational research, facilitating advances moving from bench to bedside.
The clinical arm of the research is led by Mr Kevin O’Neill who is a leading neurosurgeon and is based at Charing Cross hospital. The team have already made notable progress in the advancements of brain tumour surgery thanks to the invention of the iKnife. This
has successfully proven to accurately identify brain tumour tissue using real-time analysis during surgery, providing immediate life-saving treatment options. The UK’s first formal patient trial using the iKnife is now underway at Charing Cross Hospital. The non-invasive technique employed by the iKnife allows it to measure light reflected to determine whether the tissue is cancerous or healthy. In all cancer surgery, the aim is to remove all abnormal tissue while sparing healthy cells. This is even more important with brain tumours, as removing healthy tissue can cause permanent damage to cognition, motor function, memory and speech. This technique and clinical trial will be a huge step forward in treating brain tumour patients.
Dr Nelofer Syed is the lead scientists at the Hammersmith Campus site which focuses on laboratory research. One of the key challenges in treating tumours is that the cells within a single tumour are not identica. This is referred to as tumour heterogeneity, which means that a number of potential treatments which just target individual cell types have failed to be effective in the clinic. Therefore, her group at Imperial aims to identify biochemical events that are common to all tumour cells and use these as a potential drug target.
One approach is to target changes associated with increased energy production, which is required for the growth and multiplication of the tumour cells. The goal of the research is to identify novel drug targets that will allow us to treat this type of brain tumour that is highly resistant to current therapies.
Two strategies are being used. Firstly, glioblastoma multiforme (GBM) cells have been generated from tumour samples removed following surgery. This has allowed the researchers to identify specific energy-producing pathways that may be over-active in tumours when compared with normal nerve cells. One of these involves an increase in the use of arginine as a source of energy. The researchers have also shown that inhibition of this energy source makes the tumour cells more sensitive to the actions of drugs such as temozolomide. Current research in the lab aims to get a better understanding of how this happens and whether it could be translated into the clinic. Dr Peter Szlosarek is also carrying out a pilot clinical using the drug ADI-PEG 20 which binds with arginine, lowering its concentration in the body.
A second strategy that is being investigated exploits the fact that GBM cells have a requirement for high glucose levels. If the cells are forced to use other sources, this may decrease their growth. The ketogenic diet (KD) decreases the availability of glucose for the cells and therefore potentially decreases their energy levels. The KD is a high-fat low-carbohydrate diet and has been used in the clinic for the treatment of refractory paediatric epilepsy. The KD has been shown to have a beneficial effect on pre-clinical models of GBM including the potentiation of the effects of radiation and chemotherapies. However, the molecular mechanisms behind these effects are unknown and have largely been unexplored. A greater understanding of these is of obvious importance both to identify suitable patient subgroups for this approach and to inform potential strategies to optimise the current therapy. This is a great example of how basic science can be translated into the clinic.
In order to design a clinical trial to assess the potential effect of the KD on patients with GBM, Brain Tumour Research organised an incubator day led by Dr Matt Williams from Imperial College. It assessed the available evidence upon which a study could be based in addition to considering the feasibility of carrying out such a study. A draft protocol was agreed and work is now being carried out to develop a detailed study design.
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