Lay Summaries for all studies supported by BRAIN UK in 2015.
Glioblastoma is the most malignant primary brain tumour with only 10% of patients alive five years after diagnosis. Therefore there is an urgent need for better understanding of these tumours in order to identity new treatments.
It is becoming increasingly clear that each patient’s tumour is caused by different underlying mutations and thus there is a need for personalised molecular therapies, rather than the standard chemotherapy and radiotherapy that is currently available.
This study will examine the genetic changes within different parts of individual brain tumours and compare this with the different genetic changes that occur when the tumour regrows. This could hold the key to understanding the pathways that lead to tumour regrowth and resistance to current therapies and guide new treatment development.
Project Status: Active
Down syndrome is the most common form of intellectual disability, with a worldwide prevalence of 1 in 750 live births. In the majority of cases, Down syndrome is caused by the presence of an extra copy of chromosome 21, so that people have three copies of that chromosome, instead of two – referred to as trisomy 21. To date, little is known about how the brains of individuals with Down syndrome develop and how this may lead to intellectual disability. Using human stem cells, we developed technologies to replay how nerve cells of the main part of the brain that is affected in learning disability, the cerebral cortex, are formed during development. When we compared stem cells with trisomy 21 with those with the normal number of chromosomes, we found a major difference in how many cerebral cortex neurons are produced during development, as well as a lack of specific cell types. Our observations using stem cells in the lab predict that there are changes in the numbers and types of cells made in the developing cerebral cortex in trisomy 21, which could contribute to learning disability. In order to confirm this, we would like to analyse the numbers and types of neurons in the developing cerebral cortex in Down syndrome/trisomy 21, compared with the cerebral cortex with the normal number of chromosomes. This work could lead to a significant advance in our understanding of brain development in people with Down syndrome, and how this contributes to learning disability.
Project Status: Active
This approval was for a single patient study. The patient had died of an unusual neurological complication of a liver tumour (Posterior Reversible Encephalopathy Syndrome - PRES). The mechanism of the development of this complication was unclear. The aim of the study was to stain liver tissue for the presence of a substance (Endothelin) implicated in the pathophysiology and development of PRES to test the hypothesis that Endothelin production/secretion by the liver tumour may have had a role to play.
Project Status: Active
During embryo development, the spinal cord, vertebral column and muscles are laid down by stem cells, known as neuromesodermal progenitors (NMPs). Our group has recently found the optimal conditions for isolating and culturing NMPs in the petri dish. Interestingly, many, predominantly childhood, tumours appearing in the brain and spinal cord also consist of a mixture of neural and bone/muscle cells i.e. the natural products of NMPs. These tumours are highly malignant and difficult to treat. We wish to test whether the stem cells driving such cancers resemble normal embryonic NMPs. We will thus examine various tumour samples for the presence of NMP-like cells. If we detect the presence of these cells we will then try to isolate them from primary tumours and culture them using the conditions we have defined for normal NMPs. Our long term aim is to discover drugs that eliminate these cancer stem cells and hence block the formation of the tumours they give rise to.
Our long term aim is to discover drugs that eliminate cancer stem cells and block the formation of the tumours they cause. During embryo development, the spinal cord, column and muscles are laid down by stem cells, known as neuromesodermal progenitors (NMPs). Our group has recently found the best conditions for isolating and growing NMPs in the petri dish. Interestingly, many childhood tumours in the brain and spinal cord also consist of a mixture of neural and bone/muscle cells. These tumours are highly malignant and difficult to treat. We wish to test whether the stem cells driving such cancers resemble normal embryonic NMPs. We will examine various tumour samples for the presence of NMP-like cells. If we find the presence of these cells we will try to isolate them from primary tumours and grow them using the conditions we have defined for normal NMPs.
Project Status: Active
Approximately 7,000 patients in the UK develop primary brain tumours every year, and there are many more that develop metastases within the brain such as lung cancer, breast cancer and lymphoma. Only 10% of adult brain tumour patients are alive 5 years after diagnosis: Therefore there is an urgent need to improve clinical outcome.
Current treatment includes reducing the size of tumour by surgery, chemotherapy and monitoring for tumour regrowth via repeated imaging, which is costly and relatively insensitive.
There is good evidence in other malignancies such as breast, colorectal and prostate cancer that Circulating Tumour Cells (CTCs) can be detected in the blood and that this correlates with the presence of metastatic disease elsewhere in the body. CTCs are cells that have been shed from a tumour into the bloodstream, and which can act as ‘seeds’ for tumour growth elsewhere in the body.
If successful, my project will enable those suffering with brain tumours to have their disease progression monitored using blood samples instead of repeat surgery, which can lead to increased morbidity. It could also allow for early detection of relapse.
Once the CTCs have been identified within the blood of brain tumour patients they will be analysed for any genetic changes.
We will then explore whether our findings from our investigations on CTCs can also be seen in unlinked archival tumour tissue in the hope that it will provide us with a better understanding of tumour resistance to current therapies and may help us to find potential new therapies.
Project Status: Active
Choroid plexus tumours (CPT) are rare brain tumours and they commonly occur in children. Patients with these tumours are treated mainly by surgery. One of the sub-types of these tumours known as choroid plexus carcinoma (the most aggressive type) can recur after surgery. We don’t know of any specific additional drug treatment (chemotherapy) that is effective in these tumours. Unfortunately due to its rarity there is currently limited research published on the make-up of these tumours.
While we were testing the effects of a gene called c-Myc (which is known to be abnormal in several types of tumour) in brain tumours in a mouse model in our lab, we unexpectedly found that a significant number of animals with increased expression of c-Myc in immature brain cells developed CPTs. We also observed that a third of human CPTs express high levels of c-Myc.
We plan to see if c-Myc expression has any impact on the treatment of the patient and outcome. We want also to assess whether observations made in our mouse model are relevant in humans and if this mouse model can be used to study the human tumours counterpart. We expect these experiments would help us understand more about tumour pathology and genetics, in particular in relation to the gene c-Myc. Our ultimate goal is to investigate if c-Myc expression in CPTs would help to better predict the outcome and if patients can be selected to receive specific chemotherapy treatment.
Nb This is an extension to study 13/003.
Project Status: Active
Research Outputs: Abstract x2; Platform Presentation x3
The research to be conducted aims to determine how non-neuronal cells in the brain contribute to the detrimental events in Alzheimer’s Disease (AD) and Down syndrome (DS)-associated AD. A common feature in AD is the recruitment of non-neuronal cells, known as astrocytes and microglia, to areas of neuropathology. Studies are needed to resolve the role of these cells during early, intermediate, and late stages of AD. Using postmortem human tissue of Down syndrome patients, known to develop AD after the age of 45, our preliminary results show the involvement of glial cells in AD-related pathology. This next step of the research will be to determine how glial cells are altered during different phases of AD and DS-related AD using postmortem human tissue. From a therapeutic perspective, this proposal will provide new insight into how regulation of glial cells in the brain may provide an effective target for reducing AD-related pathology in DS.
Project Status: Active
Medulloblastoma is the most common primary cancerous brain tumour in children. This is a rapidly growing tumour with a 5 and 20 year survival of 60% and 32%, respectively. Surgical removal is the primary treatment for this tumour. Postoperative chemotherapy (type of cancer treatment, with medicine used to kill cancer cells) is additionally used but the efficiency of the current chemotherapy drug treatments is not well established. There is therefore an urgent need to better identify both key prognostic markers for this disease as well as tissue markers that may predict the child’s response to established and novel or experimental chemotherapy drugs.
Our recent studies of neuroblastoma (a common cancerous nerve tumour of children arising predominately outside the brain) have identified interactions between N-myc protein and protein arginine methyltransferase 5 (PRMT5). These are tumour promoting proteins. These two proteins are thought to act as prognostic factors and new drug targets. Similar to neuroblastomas, medulloblastomas can show changes in the MYCN gene, which encodes the N-myc protein and we presume that similar to neuroblastoma, PRMT5 can interact and influence the function of N-myc and other proteins.
Using immunohistochemistry (a technique used to detect protein presence in tissue sample), we are planning to see if PRMT5 protein and its associated protein networks are found on medulloblastoma tumour surgical samples. We will link the presence of protein with clinical data. It will allow us to begin studying these proteins as part of a larger analysis to determine their usefulness and accuracy in providing a potential drug target and more accurate prognosis for children affected by medulloblastoma.
Project Status: Active
1% of the population suffers from schizophrenia suffering immensely distressing symptoms. The illness emerges in early adulthood, leading to a severe impact on society both economically (£12bn a year in UK) and socially. More hospital beds are occupied by persons with schizophrenia than all other psychiatric illnesses combined. Much remains unknown about the mechanisms and causes of schizophrenia. As current treatment remains insufficient, a better understanding of the underlying neurobiology is mandatory to address its challenges adequately. An interaction of genetic and environmental risk factors during pregnancy is assumed to result in brain abnormalities, providing a background of susceptibility for new insults to result in brain malfunctioning.
Recent genetic and other studies suggest abnormalities of the immune system in schizophrenia. Therefore we propose that people with schizophrenia have a more sensitive immune system which is amplified during psychosis (when the patient has distorted contact with reality) seriously impacting the person’s life. We will study the immune system in the brains of schizophrenia patients who died with or without psychosis compared to control brains.
This project will generate highly novel information about the contribution of systemic and brain inflammation in schizophrenia and support future diagnostic and therapeutic developments.
Project Status: Active
Meningiomas are usually considered to be benign central nervous system tumours but a significant fraction of patients with all types of meningiomas will eventually relapse. This pilot study intends to analyse the changes in the cell surface markers and internal cellular pathways of the tumour environment and correlate these findings to specific genetic changes seen in different types of meningiomas. Eventually, these results may lead to the identification of targets in patients with different types of meningiomas, allowing therapeutic treatments to be personalised.
Project Status: Active
Recent findings in many types of tumour have shown that such tumours are made up of different cells. How these cells talk to each other drives the multiplication (proliferation) of cells that isn't normal. This effect is now seen as one of the 'hallmarks' of cancer. One of the best examples of this are tumour associated immune cells, macrophages, which drive tumour formation including cell proliferation, formation of new blood vessels and the spread of tumours. Loss of the Merlin tumour suppressor, a protein that would normally act as a brake for cell proliferation, causes lots of tumours of the nervous system, mainly schwannomas, but also meningiomas and ependymomas. Although schwannomas have been described as being made up of only Schwann cells, our work and the work of others have shown that there are large numbers of macrophages within both human tumours and in mouse models of schwannoma. Macrophages are considered to be of two types, M1 and M2, and by using markers on the surface of the macrophage cells we can identify them within the schwannoma tumours as either M1 or M2. These two types of macrophages have very different properties and by understanding the type of macrophages within these tumour, then we can tailor potential treatments to target these cells within the schwannomas and prevent their growth.
Project Status: Active
Alzheimer’s disease is the commonest cause of dementia (failure of mental function with age). In the brain in Alzheimer’s disease there are many different abnormalities, affecting many different proteins. Understanding of how the different proteins interact is limited because of technical constraints. For example, the proteins involved include Aβ, tau, apoE, which are located in different structures in the brain; inside and outside cells (including nerve cells and supporting cells) and within the walls of blood vessels. The limitation in our understanding comes about because in any one sample of brain tissue it is only possible to identify up to about 3 proteins at a time. Collaborators at GE Global Research are developing new technology called MultiOmyx which allows examination of up to 60 different proteins in the same tissue sample. This is a tremendous technical advance and has the potential to increase our understanding of the brain abnormalities in Alzheimer’s disease and other diseases affecting the brain. In this study we wish to work in collaboration to explore the use of MultiOmyx in Alzheimer’s disease, in this pilot study by using brain tissue from 6 patients with Alzheimer’s disease and 6 elderly normal subjects for comparison.
Project Status: Active
Currently approximately 9,400 patients per year in the UK (based on 2011, CRUK statistics) are diagnosed with a brain, other central nervous system or intracranial tumour; with the incidence of diagnosis and death increasing. The overall 5 year survival rate is 18.8% compared with 50% across all cancers; with 5,200 patients per year in the UK dying of this disease in 2012 - equivalent to 14 people every day ( CRUK statistics). Brain, other CNS and intracranial tumours are also the most common cause of childhood death from cancer.
This research project aims to provide translational benefit to patients by studying the genetic landscape of rare, incurable childhood brain tumours and adult brain tumours to identify multiple genomic mutations in several pathways in brain tumour formation.
This may ultimately help clinicians with diagnosis, and could also help to identify appropriate targeted treatments for these brain tumour types.
Project Status: Active
Lay Summary not yet available.
Project Status: Active
Primary glioblastoma occur in 4/100,000 per year and have a 5% five year overall survival. There is an urgent need for improved personalised drugs. A recent study revealed that patients treated with PPAR agonists (drugs used in type 2 diabetes) had a lower incidence of glioblastoma. Such drugs have been shown to inhibit the growth and spread of glioblastoma cells in the laboratory.
We aim to investigate the PPAR family of molecules as biomarkers – genetic changes in the tissue - that can provide us with more detailed information from each patient’s biopsy or surgery. This may allow us to determine which patients can receive differing therapies based on the molecular characteristics of their tumours.
Our early work has shown that the PPAR family of molecules are overexpressed in glioblastoma surgical samples compared to healthy brain tissue. This overexpression may be related to patient survival.
In order to investigate further whether this finding is true of all patients, we need to establish whether it remains true when we look at other clinical factors. These include age, how healthy patients are when diagnosed and what surgery and treatment they have received. These details will be obtained from the NHS records and stored anonymously.
Nb This is an extension to study 14/008.
Project Status: Active
The build up of waste products like amyloid plaques, which are protein pieces, in the walls of arteries is a common cause of stroke and is also commonly observed in Alzheimer’s disease. The build up of amyloid is an indicator of the brain’s failing ability to remove waste along the walls of blood vessels. Some arteries do not develop amyloid deposits but rather have enlarged spaces around them that can be observed on MRI scans. We are fortunate to have brain tissue from two patients with amyloid deposits. In this project we propose to apply our expertise in the analysis of blood vessels of the brain together with advanced microscopy to compare the structure of blood vessels in the same patient between amyloid-laden arteries and arteries with enlarged spaces around them. We will also compare this tissue with some from ‘healthy’ brains. The findings will allow to identify unique differences that will shed light on why the enlarged spaces appear around some vessels in the same patient that also has amyloid deposits.
Project Status: Closed
Dementia pugilistica or “punchdrunk syndrome” is a neurodegenerative disease associated with the repetitive traumatic brain injuries which occur in boxing. Patients present with behavioural changes, aggression, and ultimately dementia or Parkinsonism. However, it is now appreciated that a considerably larger population of individuals are affected by this condition, particularly athletes and military veterans. The more general term now used for the condition is chronic traumatic encephalopathy (CTE). The seminal study on dementia pugilsitica was published in 1973 on a series of boxers in the Corsellis collection. We recently accessed these cases and confirmed that they show the distinctive pathology now associated with CTE. The aim of this study is to look in more detail at the changes that occur in these brains, particularly around the blood vessels, to gain some insight in to the pathological mechanisms that are involved. We will be using a newly developed technique, called CLARITY, that allows the tissue to be made transparent and reveal its detailed 3D structure. Ultimately we hope to better understand the long-term effects of traumatic brain injury on the brain.
Project Status: Active
Huntington’s disease is a neurological condition that is devastating to the patients but also to their family. The onset occurs in the prime of adult’s life. The patients lose control of their movements and other complications occur such as pneumonia and heart disease. It usually ends up with dementia. It is now well established that the disease is caused by a mutation in a gene encoding for the protein Huntingtin. This latest is involved in neuronal development. It has been shown in Huntington’s disease that the mutated form of Huntingtin accumulates in the cells of the body and forms aggregates. This is linked to the severity of the disease. In our laboratory, we use a technique based on Carbon-14 dating to measure the ability of different regions of the brain to regenerate. We have been able to show recently that neurons have a slower turnover in Huntington’s disease. We would like now to extend our study by analyzing other cell types such as the oligodendrocytes as these are the most vulnerable ells of the central nervous system.
Project Status: Active
Using tissue from Brain UK we have already demonstrated that a novel enzyme named LOX is under expressed in the supporting cells in bipolar disorder. We now wish to expand upon these findings by increasing the sample size to increase statistical significance and by using sophisticated technology that could determine the origin of LOX and why it is affected in bipolar disorder.
Project Status: Active