Report on research funding 2004-2007
Report on research funding 2004-2007
Brain Tumour UK aims to find better treatments for this terrible group of diseases through our programme of research. Since 2004 we have been involved in the joint funding of four research projects with the Samantha Dickson Brain Tumour Trust. We are proud to have contributed £250,000 towards these projects which have now been completed; research papers are currently being written for medical journals. All of the projects have provided excellent information, and, for some tumour types, this will lead to more effective treatment in the future.
Please see below for a summary of the four research projects that Brain Tumour UK helped to fund from 2004-2007.
Future research funding plans
Our Board of Trustees are currently reviewing and developing Brain Tumour UK’s future research funding plans. We will update our website with news of the new funding plans in 2008. The generous donations we have received in the past have enabled us to help progress medical research and knowledge of brain tumours, their causes and treatments; please continue to give us your support.
Molecular characterisation of 12 differentially expressed
genes identified by microarray analysis in paediatric ependymoma
by Dr Tracy Warr
Brain tumours are the most common form of solid cancer in children and a significant cause of death in children younger than 15. Ependymomas are the third most common type of paediatric (child) brain tumour.
The majority of tumours do not respond well to radiation therapy or chemotherapy.The outcome for patients with ependymoma is poor, with 5-year survival rates of 34-45%.
The most likely reason for the relative lack of progress in treating these tumours, compared to improvements in survival of other childhood cancers, is the lack of understanding of the biology of paediatric brain tumours.
Tumours arise when certain types of genes are damaged.This damage can cause some classes of genes to become overactive (called overexpression). Other types of genes, such as growth-inhibitory tumour suppressor genes, may become inactive (called underexpression).
Until recently we did not know which genes were involved in the development of ependymoma. However,we have now identified 12 which appear to be inappropriately turned on or off in these tumours, and may contribute to tumour development. In this project we will investigate the mechanisms by which these 12 genes are damaged, in order to determine whether they can be used in the development of new therapies.
Glioblastoma Multiforme: toxin delivery
by Professor John Darling, Dr Iain Nicholl and
Dr John Howl
Research Institute in Healthcare
Science, University of Wolverhampton
Malignant brain tumours like glioblastoma multiforme (GBM) are very hard to treat. Surgical removal is impossible and the tumours are resistant to radiotherapy and chemotherapy. GBM continues to provide a formidable clinical challenge.The median survival of patients with GBM is still only around 6-9 months and less than five per cent of patients remain alive two years after diagnosis.
There is a need for new types of therapy based on a better understanding of the biology of these tumours and to develop ways to selectively deliver toxins to tumour cells. Professor Darling and his colleagues intend to make small chains of amino acids, the building blocks of proteins, called peptides.The laboratory will identify three different specific receptors present on the tumour cells, and manufacture "cell-penetrating peptides" that bind to proteins that are over-expressed on GBM cells and then deliver toxic cargo molecules into the centre of the cancer cells to kill them.
Preliminary experiments
Three classes of cytotoxic drugs will be examined: temozolomide, carboplatin and a peptide containing a PCNA-binding motif that has been shown to interfere with cell growth. Preliminary experiments have shown that this approach is possible. Peptide constructs can be made which are about 100-fold more toxic to GBM than non-specific toxic peptides.
This project will provide a systematic study to identify the most effective toxin and the most effective cell-penetrating peptide to target GBM cells. It will also identify how these might be combined to produce promising hybrid peptides for eventual use in patients in clinical studies.
Pituitary tumours: silent genes
by Professors W.E. Farrell and R.N. Clayton
The pituitary gland lies deep within the brain and is frequently referred to as "the master gland" since it controls many body functions. Pituitary tumours account for between 10 and 15% of all brain cancers.
Many will be relatively benign, but about one third invade other parts of the brain and many, despite surgical removal, recur. Less frequently they may also spread to other parts of the body, however, it is not known why these tumours show these different growth characteristics. In common with many other tumour types, the events that underlie the initiation and progression of these tumours involve changes in our genes. One of these changes - termed methylation - leads to the silencing of particular genes.
If this silencing occurs in genes that, for example, normally tell cells to stop growing, then this may result in uncontrolled growth - a tumour. In other cancers, it has been shown that this change in methylation may silence hundreds of genes within a particular tumour type.A key question is: how do we find these genes? Fortunately, there are drugs that reverse this change so that the genes are no longer silenced but expressed. However, this raises the question: which genes were silenced and are now expressed?
Analysis
This study will grow pituitary tumour cells in the presence of a drug that will cause silenced genes to be re-expressed.This will allow us to determine the identity of these genes using a technology termed Microarray analysis. Thus, it will be possible to look at the vast majority of genes that are expressed normally and ompare these to those expressed in a tumour. Not only will this show which genes are silenced, but also which are switched back on by the drug.
For technical reasons these experiments are only possible using pituitary tumour cell lines and not actual tumours.Therefore, the next part of the study will use a very large panel of pituitary tumours derived from patients and - gene-by-gene - identify those that are silenced, it will then be possible to find out if this silencing is associated with this process of methylation. The first task will be to determine how many of the human tumours show changes in methylation and which genes are affected. It will then be determined if it is an early or a late change, if particular types of pituitary tumour share the change or if the change defines particular tumour subtypes.
It will then be determined if these changes are able to show those tumours that are destined to show aggressive-invasive growth or those that are likely to recur.Thus, these findings are defining the molecular pathology of a tumour and may be used, alongside other techniques, to make important decisions as to how patients are managed clinically. These studies will allow definition of a panel of genes that will become part of a routine assessment procedure after surgical intervention. It may be possible to predict tumours that are benign and require no further management, those that are invasive, those that are likely to recur and indeed those that will grow beyond the brain in the process of metastatic spread.
Quality of life
by Dr. Colin Kennedy, Southampton
Previous studies of the psychosocial consequences of childhood cancer for the child and their parents have used a variety of methods focusing mainly on negative outcomes of the cancer experience. On the whole these studies have found that children and parents cope well. However, few focused on children with brain tumours even though they may well differ from children with other types of cancer.
Children and parents do not necessarily share the same views on the impact of the cancer experience. It is important to try to understand why, and what effect such a difference may have on the child's quality of life. It is possible that parental distress negatively affects parents' perceptions of the child's emotions and behaviours. It is therefore helpful to get a more independent view of the child by asking a teacher.
Parental distress may also affect the child's well being. When studying the child's quality of life, it is important to find out how parents perceive the cancer experience and whether this reflects a general attitude or a passing phase. It is also important to assess parental coping strategies as these may have a mediating effect not only on their own quality of life but also on their child's quality of life.
One of the problems with using standardized questionnaires is that they may not be sensitive enough to detect more subtle effects of the cancer experience. If done on only one occasion, the answers may only reflect how the child is at that moment though the effects of the cancer and its treatment on the child may well change. A method of investigation that has been largely neglected is interviewing. This allows researchers to find out how the cancer experience has affected quality of life from the participant's own point of view. People may be inclined to be more truthful during a face-to-face interview than on a questionnaire. This research will study three groups of children and their parents over time. Two of the groups will have experienced serious illness resulting from two different types of brain tumours and the third will be a group who have not experienced these problems. The aim is to see if children with a brain tumour have a poorer quality of life, whether it varies with the type of brain tumour and whether it changes. This information could then be used to help children and parents who are more negatively affected by the cancer experience.
Current links
Cellular and molecular neuro-oncology at the University of Portsmouth www.port.ac.uk/brainlab
Brain Tumour UK hopes to establish links with all major UK research centres in due course.
