SAMANTHA DICKSON BRAIN TUMOUR TRUST

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SAMANTHA DICKSON BRAIN TUMOUR TRUST

  1. 1. _____________________________________________________________________ Samantha Dickson Brain Tumour Trust, New Research Projects Funded in 2006 - 1/7 SAMANTHA DICKSON BRAIN TUMOUR TRUST Century House, High Street, Hartley Wintney, Hants. RG27 8NY. Tel: 0845 130 9733 e-mail: sdrt1996@aol.com www.braintumourtrust.co.uk NEW RESEARCH PROJECTS FUNDED IN 2006 A Genome wide Methylation Analysis of Oligodendroglial Tumours Dr Koichi Ichimura, The University of Cambridge Summary: to identify abnormally methylated genes that due to aberrant methylation are involved in the development of oligodendrogliomas and that may also determine their response to therapy. Using newly developed microarray techniques that will allow the analysis of the methylation status of thousands of genes in one experiment, we intend to identify such aberrantly methylated genes. Once candidate genes are identified by being present as a single copy and showing an abnormal methylation pattern, they can then also be analysed for mutation in tumours that also have only one copy of the gene but without abnormal methylation. By using advanced techniques with customized tools, it is hoped to identify genes responsible for development, progression and drug sensitivity of oligodendrogliomas. The identification of these genes will help us understand the mechanism by which the tumours develop and may also explain why some of these tumours respond to therapy better than others. The identification of the genes involved could thus provide new ways of predicting therapy response, may assist in identifying new groupings of oligodendroglial tumours providing prognostic information as well as building the basis for specific, effective, targeted, molecular therapies. Reassessing the origins of cranial Germ Cell Tumours (GCTs) Dr Paul Scotting, The University of Nottingham Summary: Most adult cancers arise through the slow accumulation of damage to genes. Given the early age at which these GCTs occur, these brain cells might be activated to grow as cancers, by non-genetic mechanisms (methylation and acetylation) that do not generally involve damage to their DNA. Indeed these cancers are typified by unusual alterations in DNA methylation. These alterations may be more readily reversible than the genetic damage seen in most cancers. In this study we will carry out experiments to determine which neural stem cells of the brain are indeed able to give rise to GCTs and to investigate the role of methylation and acetylation in this process. The aim of these studies is to establish which brain cells are the most likely origin for cranial GCTs and at the same time begin to establish an experimental model in which to dissect the molecular mechanisms through which they are formed. While current treatment of older teenagers with germinoma is very successful with limited (but significant) side effects, new approaches are needed for younger patients and those with other GCT subgroups, where treatment is relatively unsuccessful.
  2. 2. _____________________________________________________________________ Samantha Dickson Brain Tumour Trust, New Research Projects Funded in 2006 - 2/7 Detailed analysis of two genetically altered regions of the genome in astrocytic gliomas by means of chromosomal tile path array-CGH Professor Peter Collins, University of Cambridge Summary: This project analyses the genetic abnormality of astrocytic gliomas in adults and children. It focuses on the altered chromosomes 7 and 10 in these tumours. The investigation will be at a level previously not possible, and the department has a unique collection of over 300 astrocytic tumours that have been extensively studied for abnormalities over the last 10 years. The aim is to identify so far unidentified genes on chromosomes 7 and 10 that are involved in the progression of these tumours. This study will help us to better understand the biology of this group of devastating brain tumours. The identification of the genes involved will assist in identifying new subgroups of this tumour type which will help with prognosis as well as more effective targeted treatments. Radiological and Molecular markers of subsequent behaviour in adult low-grade tumours Dr Tracy Warr, Institute of Neurology, London. This project is being funded by the SDBTT Astro Fund Summary: Low-grade gliomas (LGGs) are slow-growing brain tumours that usually affect children and young adults. In adults, but not in children, many of these tumours eventually turn malignant after a period of anything between one and ten years. This process, called malignant transformation, seems to occur unpredictably and eventually causes severe disability and even death. To date no treatment has been shown to prevent malignant transformation and so the majority of patients with LGGs are only treated when the tumour has started to cause neurological disability. Our understanding of how these tumours behave is hampered by the obvious problems of sampling the tumour at different times in the patient’s life. In order to circumvent this problem, we have chosen to study LGGs using state of the art imaging called Magnetic Resonance Imaging (MRI) and to develop a range of computerized methods to analyse the scans and to look at different aspects of the tumours behaviour. We are now hoping to extend the study by analysing samples from the patients’ tumours using a variety of laboratory methods which tell us about the genes and the proteins in individual tumours. In this way we hope to improve our understanding of what changes occur in these tumours before they turn malignant both at a level visible by scanning as well as at the level of individual cells and molecules. By doing this we would then be able to identify patients who are at risk of malignant transformation before they come to any harm through rapid tumour growth. In this way we hope to see whether it is possible to identify more aggressive tumours early on and thereby treat the patient at an earlier stage than we would otherwise have done. In so doing we would hope to be able to reduce neurological disability, improve quality of life and even possibly overall survival.
  3. 3. _____________________________________________________________________ Samantha Dickson Brain Tumour Trust, New Research Projects Funded in 2006 - 3/7 Advanced magnetic resonance imaging and metabolic studies of Low Grade Gliomas of childhood Professor Richard Grundy, The University of Nottingham This project is being funded by the SDBTT Astro Fund Summary: The biology and natural history of low grade (pilocytic) glioma affecting the optic pathway is of particular interest. Most commonly presenting in the first 5 years of life these tumours frequently cause considerable morbidity, particularly visual impairment and endocrine damage. The natural history and clinical evolution of this disease is very difficult to predict. Overall tumour growth is slow, but may be punctuated by episodes of more obvious tumour growth. Frequently there is a discrepancy between MRI appearances and changes in important clinical factors such as visual function. The decision over when to start therapy, or indeed to stop is difficult in the absence of any objective evidence of the clinical behaviour of the tumour. For the majority of patients there are currently few clinical predictive characteristics. It would be of particular value if Magnetic Resonance Spectroscopy could identify biological characteristics which predicted quiescence or progression. In cases where chemotherapy or radiation therapy is used it would also be of value if we could detect the biological significance of residual imageable disease during and at the end of such treatment. It would also be useful if FI could be used as a method of surveillance predicting changes in tumour behaviour. We aim to study these important questions in this study. UK Case control study of possible causes of brain tumours in children, teenagers and young adults: A pilot study Professor Patricia McKinney, University of Leeds Summary: The causes of brain tumours are unknown but it is important to isolate either genetic or environmental factors so that efforts can be made to prevent the disease. No research in the UK has previously been dedicated to investigating both the genetic and environmental causes of these conditions. A previous study from the early nineties, the UK Children’s Cancer Study, was relatively small and did not investigate genetics or include those over 14 years. New studies investigating the causes of brain tumours in children are planned and underway in other countries of the world. A new large-scale study of the causes of brain tumours in children, teenagers and young adults is being planned in the UK in collaboration with the UK Children’s Cancer Study Group (UKCSG) and the Teenage Cancer Trust. Possible causes to be investigated include genetic susceptibility, viruses and infections, use of mobile phones and exposure to radiofrequency fields, diet and associations with malformations present at birth. This type of research has to include large numbers of patients diagnosed with brain tumours as well as a comparison group of healthy controls. These studies are both comprehensive and expensive and require established procedures, which involve a large number of treatment centres and their clinical staff. The final study will collect information which is the same as in other international studies so eventually data can be pooled for powerful analyses of the causes of these tumours.
  4. 4. _____________________________________________________________________ Samantha Dickson Brain Tumour Trust, New Research Projects Funded in 2006 - 4/7 Wnt signalling in Neural Stem Cell differentiation and Tumourigenesis of the CNS: Initial Study Professor S. Brandner, Institute of Neurology, London Summary: Activation of the wnt signalling pathway stimulates growth and mediates development signals between cells. Wnt signal transduction involves well-characterised tumour suppressors and oncogenes such as adenomatous polyposis coli protein (APC) and ß-catenin and plays an important role in embryonic development, differentiation, and in tumourigenesis. Constitutive activation of wnt signalling, either by APC loss of function or by ß-catenin gain of function, can result in a variety of tumours and tumour syndromes, including malignant brain tumours. We have shown that inactivation of other tumour suppressor genes in the subventricular zone (SVZ) stem cell compartment in adult brains leads to a specific type of brain tumour. Here we will investigate whether activation of ß-catenin in these stem cells can alter their proliferation and fate and whether this activation is sufficient to elicit brain tumours or if inactivation of additional genes, such as p53 or PTEN is necessary. Further, we will also determine the cellular and molecular basis of the early lesions that develop in the SVZ prior to tumour formation. In this project, we are combining questions of stem cell biology, their relevance to brain tumour formation and correlation to phenotypic characteristics of these brain tumours. This unique combination of biological techniques will enable us to understand fundamental concepts of stem cell biology and tumourigenesis in the central nervous system. With this model, we are developing a paradigm to study the contribution of specific pathways to the development of brain tumours for neural stem cells. Ultimately this model will be an important tool to systematically study and to understand tumourogenesis in the central nervous system. Imaging of molecular dynamics and cell fate to identify new targets for Medulloblastoma therapy Dr. V. Sée, University of Liverpool Summary: This study will be conducted at the cellular level, initially using medulloblastoma cell lines. We propose to investigate the way in which these cells interpret signals in their environment and how the responses to these signals are different from non-tumour cells. We are especially interested in the ways in which signal timing can affect cell responses in medulloblastoma. Through looking at three sets of proteins (E2F, p53 and NF-ĸB) that respond to signals and further control the activation of genes, we hope to better understand how normal and medulloblastoma cells display a different balance between cell differentiation or division (which underlies this cancer). Through understanding how these critical switches go wrong, we hope to be able to see how well current chemotherapy treatments work and why they fail in some cases. The ultimate aim will be to identify new molecular targets and therefore improve treatment strategies. The project involves an interdisciplinary collaborative team of basic scientists, surgeons, pathologists and physicians. We will make use of state-of-the-art technical expertise in advanced single cell imaging through the unique microscopy facilities in the Centre for Cell Imaging in Liverpool. Using these techniques, we have already developed assay measurement of signalling, gene expression and cell fate in living cells. Finally, we will apply what we learn with cell lines to investigate the responses in tissues and in primary cells grown from fresh tissue obtained from medulloblastoma patients. We can then compare responses in the laboratory to the ultimate disease prognosis, thus ensuring clinical relevance of our experimental work. Our expertise in growing
  5. 5. _____________________________________________________________________ Samantha Dickson Brain Tumour Trust, New Research Projects Funded in 2006 - 5/7 primary neuroblastoma cells, combined with our knowledge in cell imaging, offers an exciting opportunity in applied medulloblastoma research. Development and evaluation of a neuropsychological follow-up service for survivors of childhood brain tumours Professor Christine Eiser, University of Sheffield Summary: Advances in treatment have led to much improved survival rates for children with cancer, with approximately 80% being ‘cured’. Treatment of brain tumours in children remains more difficult as survival rates remain lower than for other cancers, and approximately two thirds of children experience late effects as a result of the initial cancer or treatment. These include physical problems (for example poor growth, infertility, mobility, visual or hearing problems) as well as learning and behaviour problems. Children may look different (smaller, overweight, delayed pubertal development) and can experience teasing from others. These difficulties are a significant concern for children, their families and schools. Health, Education and Social Services are poorly equipped to address the rehabilitation needs of these children and many families lack help and support. In this proposed research, we attempt to define the extent of the problem in a group of children treated for brain tumours, and to introduce an intervention service for those with severe cognitive (learning) problems. Currently, NHS resources are targeted at medical cure of the cancer. Our argument is that children need specialist support after treatment in order to achieve their potential and enjoy a normal quality of life. Our results will be used i) to support an application for NHS funding to establish a model of service delivery for future children and ii) inform the development and structure of a national rehabilitation service. Genome-wide analysis of (childhood) Ependymomas and Pilocytic astrocytomas Professor V.P.Collins, University of Cambridge Summary: We have collected tumour cells removed at surgery from 46 patients who had Pilocytic Astrocytomas and 48 patients who had Ependymomas. All the patients or their parents have given consent and ethical approval for the study has been obtained. We know that abnormalities of the genetic material (DNA) in a cell can lead to the cell starting to divide in an uncontrolled way and thus give rise to a tumour. Studies of the DNA in many different adult tumours have led to new ways of identifying the tumours earlier, and with greater certainty, and more recently to the development of new specific treatments that do not harm normal cells. In the past in one experiment we could only study the DNA either collected in large pieces known as chromosomes and where we could only identify very large abnormalities or at the molecular level in a very few small regions at a time. With the array-CGH technology we can, for example, easily examine 3000 regions of the tumour cell’s DNA at the same time and know exactly the genetic sequence we are studying and the genes that are localised there. Thus we can get very detailed information about any changes that have occurred and identify even small changes in a way that only a year ago would have been impossible. We will first look at the tumour DNAs at intervals of 1 million bases (the letters that form the genetic code) covering all areas. Then if we find any abnormalities that are common to the tumours we will increase the resolution of the study to detect any abnormalities larger than 100,000 –
  6. 6. _____________________________________________________________________ Samantha Dickson Brain Tumour Trust, New Research Projects Funded in 2006 - 6/7 200,000 bases. We can then study the genes that have been recognised as possibly involved at the single base level and identify whether there are any abnormalities in the gene code. Genes code for the proteins that form the components of the cellular machinery. It is when the code that determines the structure of one of these components is incorrect or lost that the cell’s normal function becomes inoperative and cells start to divide in an uncontrolled way, leading to a tumour. If we knew the genes that were involved in the development of pilocytic astrocytomas and ependymomas this could help us identify these tumours with greater certainty (in some cases it can be very difficult to make the diagnosis), and we could target the mechanisms that the proteins coded by these genes are involved in to either block the mechanism if it is out of control in the tumour cells, or find ways of reviving it if it is non-functional. The contribution of drug resistant cancer stem cells to Paediatric Brain Tumours Dr Beth Coyle, University of Nottingham The aim of this project is to identify the reasons behind children’s brain tumour drug resistance and hence to provide the basis for rational strategies to overcome it. The rationale for our research relates to the “cancer stem cell hypothesis”. This theory states that the tumour itself is generated from a small population of cells (cancer stem cells) which have the ability to divide indefinitely and to develop into the different cell types that are necessary for tumour growth and invasion. Whilst in the final tumour there may be as few as one cancer stem cell per l000 tumour cells, one of the most important features of a cancer stem cell is its putative ability to resist drug treatment by actively pumping the drug out of the cell. If the cells from which a tumour arises are drug resistant then these will survive chemotherapy and repopulate the tumour even if the vast majority of tumour cells have been killed by the drug treatment. Thus, a recurrent tumour would contain a higher proportion of drug resistant cancer stem cells and be harder to treat than the original tumour. To date, cancer stem cells have been identified in three different types of children’s brain tumours, namely medulloblastoma, glioma and ependymoma. However, the role of cancer stem cells in drug resistance of these tumours has not been characterised. In the current proposal we seek to extend research specifically into cancer stem cells isolated from tumours that are chemo-resistant, namely ependymoma, high grade glioma and sPNET. We will work with established cell lines as well as cell lines newly generated in-house that we will characterise in depth. Our initial objective is to identify and isolate cancer stem cells from these tumours. Importantly, we will then demonstrate that these cancer stem cells have the two key characteristics that would enable them to cause tumour drug resistance. Firstly, we will confirm that they have the growth capabilities described above. Secondly, we will analyse their drug pumping ability and we will identify which proteins are responsible for this drug transport. We will then determine whether drug treatment of tumour cell lines leads to an increase in the proportion of cancer stem cells. Finally, we will examine the proportion of such cells in samples of primary and recurrent tumours from the same patients to see if their numbers are increased at relapse. Thus we hope to determine the nature of the population of cells which are at the roof of these three difficult to treat brain tumours and thereby facilitate the future development of more effective treatments. Comprehensive Mapping of Gene Expression and Genomic Gains and Losses in Paediatric High Grade Gliomas A Joint study between UKCCSG and PBTC consortium of North America Professor Richard Grundy, University of Nottingham
  7. 7. _____________________________________________________________________ Samantha Dickson Brain Tumour Trust, New Research Projects Funded in 2006 - 7/7 Summary: There is now mounting evidence that genetic alterations in adult HGG, Glioblastoma multiforme (GbM), are rarely seen in the paediatric GbM population, indicating that the paediatric disease must be considered independently. This study will take an unbiased, global approach to explore changes in the genome and transcriptome of paediatric HGGs and is a promising avenue of investigation that should lead to discovery of previously unknown mutations that contribute to tumourigenesis, as well as classification of tumours that may reflect prognosis or response to specific treatment regimes. In this project, gene expression studies will be undertaken using Affymetrix systems technology – comparing and contrasting the molecular fingerprints and genomic imbalances of primary and relapsed paediatric high grade gliomas. The team will validate detected genetic alterations and correlate with histopathological and clinical parameters and in turn link genetic changes with patient age, location, histopathology and patient outcome, thereby developing a biological basis for diagnosis, prognosis and treatment monitoring. Finally, they will investigate the biological significance of the observed genetic alterations by examining the spatial and temporal expression of candidate genes during normal development. Combined resources will also facilitate downstream data and functional analysis, which will in turn lead to improved treatment and patient survival. Pathways ll – Introduction of guidance to shorten symptom interval and enhance access to diagnostic pathways for CNS tumours in children and young adults, and evaluation by prospective observational cohort study Professor David A Walker, University of Nottingham The diagnosis of a brain tumour in a child or young person devastates the lives of the patient and the family because of the life threatening and disabling implications of the diagnosis. The clinical signs and symptoms that herald the diagnosis are diverse, often fluctuating in severity and differing according to the age and stage of development of the child. Diagnosis is disarmingly simple to achieve with CT or MR imaging. However, there has been an historic, recognised, under-provision of NHS imaging resources, inevitably influencing access to CNS imaging which, in paediatric practice, is compounded by the need for the scans for many to be performed with the help of sedation or anaesthesia for which resources are restricted to specialist paediatric centres. Referral guidelines have been provided by the National Cancer Plan, the UK National Collaborating Centre for Primary Care and the National Institute for Clinical Excellence (NICE), the endpoint of which is onward referral, not imaging. To date, these guidelines for CNS tumours in children and young adults have not been the subject of special mention or evaluation in primary or secondary care. Most CNS tumours in children and young adults are diagnosed as an emergency when clinical condition is critically deteriorating rather than through the two week wait cancer referral process. This project is essential for the successful conclusion of the overall aims of the Pathways Project. The enhanced brain tumour registration database is an absolute requirement for assessing the impact of the guidelines in reducing symptom interval. This much-needed database will be a major asset for future projects linked to epidemiology, genetics and health services research linked to CNS tumours.

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