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Lay Summaries for all the studies supported by BRAIN UK within the past 12 months.

BRAIN UK Ref: 19/001
Molecular analyses of glial and glioneuronal tumours by DNA methylation profiling and next generation sequencing (NGS)
Prof Andreas von Deimling, University Hospital Heidelberg

We want to improve the way brain tumours are diagnosed. Currently clinicians make a diagnosis by looking at a tumour tissue under a microscope but cannot always identify the correct diagnostic category patients should be placed into. In about a quarter of the brain tumour cases using an algorithm has made a different diagnosis, which has significantly changed the treatment of some of our patients. It is predicted that a deeper look into these tumours will significantly improve the clinical management of patients with CNS tumours and open the doors towards possible options for novel targeted therapies.

This study will provide tissue which will be used to improve a recently established computer based algorithm that can better diagnose tumours arising within the central nervous system (CNS). Here, patterns of chemical tags (DNA methylation) are detected within the tumour. This new technique will enable doctors to place patients more precisely into specific risk groups and make more accurate therapy decisions.

Our centre has previously contributed to the development of the brain tumour classifier– one of only two centres in the UK to use it. Patients treated at UCLH/NHNN have already benefitted from this novel technology and the clinical team (pathologists) have contributed to identifying DNA methylation patterns in rare brain tumour classes.

In the present study we want to contribute again to this novel and exciting development, which will significantly improve the way we diagnose tumours within the CNS and identify new diagnostic biomarkers as well as potentially targetable alterations.

Project Status: Active

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BRAIN UK Ref: 19/002
Molecular analyses of adult brain tumours by conventional molecular tests and DNA methylation profiling
Prof Sebastian Brandner, University College London 

In this study we will analyse a range of brain tumours for which no conclusive diagnosis existed, or for types of brain tumours which benefit from a more refined classification using so-called methylation arrays.
The methylation arrays detect small chemical changes in the DNA of the tumour. Such chemical changes also exist in normal tissue but is different from the changes seen in normal tissue in the brain. The pattern of these changes have been used to establish groups of tumours based on this fingerprint on the DNA (also known as epigenetic changes).
The changes of this pattern on individual tumours will be compared with a large comparison group that has previously been identified and has been in-depth characterised.
The study has two purposes: to analyse data of methylation arrays that have previously been performed, as part of the diagnostic procedure. The second purpose is to find out more about tumours that cannot be diagnosed satisfactorily, or where patients had an unexpected clinical development. This way we are trying to better understand what the nature of the tumours were. Eventually, this technique will enable doctors to allocate patients into a risk group and, importantly, make more informed and accurate therapy decisions.

Project Status: Active

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BRAIN UK Ref: 19/003
Predicting recurrence/regrowth of non-functioning pituitary adenoma by a combination of patients' clinical, biochemical, radiological and immunohistochemical outcomes.
Dr Stephanie Baldeweg, University College London 

The pituitary is a tiny gland, the size of a pea, which lies deep within the base of the brain. It acts as the “master gland” of the body, and stimulates other glands to produce hormones. Tumours within the pituitary gland are usually treated with surgery, and this is typically done through the nose using the so-called “transsphenoidal” approach.  Although usually successful, in some cases removing the entire pituitary tumour is challenging and regrowth can occur. To this end, we want to analyse pituitary tumour tissue that has already been removed by surgeons to see if their molecular characteristics might have provided a clue as to their future behaviour and recurrence. 

Project Status: Active

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BRAIN UK Ref: 19/004
Validation of histopathological findings in HTRA1 mutation carriers
Prof Martin Dichgans, Klinikum der Universität München, Munich, Germany

Stroke is the leading cause of long-term disability and the second most common cause of death. In about 20% of cases stroke is caused by changes in small brain vessels. Inherited defects in a gene called HTRA1 are a rare cause of stroke because of changes in brain vessels. We recently found in a mouse model that inherited defects in this gene cause deposition of specific proteins in brain vessels. To better understand what role these proteins have in humans we plan to investigate brain specimens from patients who have inherited a defect in HTRA1 gene. From these studies we expect to obtain a better understanding how other types of stroke develop.

Project Status: Active

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BRAIN UK Ref: 19/005
Spatial subtyping of glioblastoma using in situ sequencing (ISS)
Prof Mats Nilsson, Stockholm University, Sweden 

Over the last 10 years it has been established that malignant tumours are not just large numbers of tumour cells that are similar to each other, but instead that there can be large differences between different regions and even between different groups of cells within the tumour. This has been called “tumour heterogeneity”, indicating that there are difference between individual tumour cells. Modern gene analysis methods can now find out how many different types of cells there are in the tumour and what type of genetic faults are within those tumour cells. In addition to point mutations (changes of single elements in the DNA), there are far more complex changes in the genes of cancer cells. The usual way of doing these tests is to mix tens of thousands of such tumour cells and do computer-based analysis. However, this will simply tell us how many cells with certain mutations are in the tumour. We will not learn how these are actually distributed, i.e. whether there are found across the entire tumour or a small islands only.

Our laboratory in Stockholm (Nilsson Group affiliated to Stockholm University at Stockholm’s Science for Life Laboratory) has developed a method which allows us to analyse exactly that: with colour-coded artificially engineered fragments of DNA (like a bar-coded fingerprint) we can literally see how cells with a certain mutation are distributed across the tumour. With this methodology we can for example look at a tumour from the first operation and see how a tumour after the second operation, for example after accumulating more mutations, has developed. We can also see how certain clones of tumour cells have disappeared or expanded. This will give us valuable information about therapy response in patients with gliomas.

Project Status: Active

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BRAIN UK Ref: 19/006
Quantitative analysis of brain vascular pathology in cerebrovascular cases of the Corsellis Brain Collection
Prof Raj Kalaria, Newcastle University NHS Hospitals Trust 

The West London NHS Trust has provided 240 cases of fixed brain tissue from the Corsellis Collection, a historic collection dating from 1950’s to the 1990’s which has now been disbanded.  Newcastle will use the tissue to quantify the extent of brain vascular pathology in terms of the number and location of strokes of different sizes, small bleeds and large brain haemorrhages.  We, specifically aim to address the following questions:

1) Is the distribution of cerebrovascular changes (changes affecting the flow of blood through the brain) in the older Corsellis collection different from that in the more recent Newcastle collection from the Cognitive Function After Stroke (CogFAST) and Vascular Dementia (VaD) studies? 

2) What are the frequencies (and degree of artery narrowing) of intracranial atherosclerosis and arteriolosclerosis (the thickening and stiffening of the arteries due to the build-up of fats, cholesterol and other substances in and on your artery walls (plaque), which can restrict blood flow)?  The comparison would be in brains from the Corsellis collection and the cerebrovascular cases (participants who have strokes and other brain and blood vessel conditions) in Newcastle, collected two decades later.  This may relate to changes in discernible vascular health and lifestyle factors.  

3) Determine frequencies of cognitive impairment no dementia (individuals whose cognitive functioning falls below normal but who do not meet dementia criteria) and dementia cases in the Corsellis collection with those in the CogFAST and VaD studies to determine thresholds for dementia. The study will help us define the critical causes of brain vascular changes which cause dementia. 

Project Status: Active

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BRAIN UK Ref: 19/007
Pathological and genetic study of an unusual case of alpha-synucleinopathy
Prof Janice Holton, University College London 

In a group of diseases known as α-synucleinopathies an abnormally sticky protein called α-synuclein forms clumps inside brain cells causing nerve cells to die. The most common disease in this group is Parkinson’s disease (PD) but there is also a rarer form called multiple system atrophy (MSA). PD and MSA do not usually occur in families but there are rare instances of familial PD caused by alteration (mutation) in the gene that codes for α-synuclein protein. One clue that there may be a mutation in this gene is the finding of an unusual pattern of α-synuclein inclusions when the brain is examined. We have observed an unusual pattern of these changes in a single case and would like to investigate this further to determine whether it is due to a gene mutation. Study of rare cases has often enabled us to have a better understanding of common diseases. We hope that by performing a detailed study of pathology and genetics in this single case we may gain insight into the mechanisms causing PD and MSA. This would be very important for this group of people who have progressive disease with no currently available treatments that can alter the disease course.

Project Status: Active

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BRAIN UK Ref: 19/008
C1q in Huntington’s disease
Prof Roxana Carare, University of Southampton

Huntington's disease is a devastating genetic progressive brain condition with no cure, that affects people in their young adult life who develop uncontrolled movements, emotional and thinking problems. A key feature in Huntington’s disease as in many other brain diseases is inflammation. A product of inflammation is C1q which triggers a cascade of events that harm the brain. We want to test whether a new compound (antibody) that is developed against C1q is specific to the C1q in Huntington’s disease human brains. Annexon Biosciences is a company that has developed the compounds that target C1q that seem to have favourable effects in other neurological conditions. We propose to compare the Annexon compounds against commercially available markers of C1q in a very small set of 3 Huntington’s disease brains. If the results appear meaningful, we will increase the size in a future study with statistical power and we will also complement with other experimental methods in the lab. Long term, the aim is to develop the antibodies against C1q produced by Annexon, to ameliorate/slow down the progression of Huntington’s disease. 

Project Status: Active

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BRAIN UK Ref: 19/009
Characterisation of the Glioblastoma Immune Microenvironment
Dr Paul Mulholland, University College London Hospital

Lay summary not yet available.

Project Status: Active

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BRAIN UK Ref: 19/010
Investigating a role for dystrophin in survival outcomes of low grade glioma patients: a pilot study
Dr Karen Anthony, University of Northampton

Low-grade glioma (LGG) is a type of brain tumour that typically occurs in early adulthood. LGG patients usually survive a decade or more, although there is a high risk of treatment-related complications. Most LGG tumours grow slowly, but some grow fast and these patients have a particularly poor prognosis. To better predict an individual’s prognosis and identify the most effective treatment and management strategies, there is a need to accurately identify these patients and the features responsible.

This project investigates a potential predictor of poor patient survival in LGG. Our preliminary work indicates that patients who have a high level of a protein called dystrophin in their tumours may have a four-fold decrease in survival time. This project will use brain tumour tissue from LGG patients to confirm our findings. Our work could lead to the development of new screening tests for LGG to identify individuals with a particularly poor prognosis and to better improve the management of the disease for these individuals.

Project Status: Active

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BRAIN UK Ref: 19/011
The purinergic P2X7 receptor as drug target for refractory status epilepticus
Dr Tobias Engel, Royal College of Surgeons in Ireland

Severe seizures, which last for more than 5 minutes, are known as status epilepticus. This is a medical emergency and the priority is stopping the seizure activity. Approximately 30% of patients, however, are resistant to drugs designed for stopping seizures. We have found that, in mice, a particular receptor - P2X7 - contributes to this drug resistance. Further, we have also shown that P2X7 is increased in conditions that are often related to increased resistance to anti-seizure drugs, such as inflammation in the body. It is unclear, however, whether the findings in mice are also true for humans. The first step towards investigating this is to see whether patients who showed resistance to anti-seizure drugs have a higher than normal amount of P2X7. This would suggest that P2X7 is also involved in drug-resistance in humans and would back the idea that developing treatments targeted at P2X7 may be useful for breaking drug-resistance in these patients.

Project Status: Active

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BRAIN UK Ref: 19/012
Impact of EZH2-regulated H3K27 methylation on microglial pro-tumoral activation in Diffuse Intrinsic Pontine Glioma
Prof. Bertrand Joseph, Karolinska Institutet, Stockholm

Diffuse Intrinsic Pontine Glioma (DIPG) are aggressive and primary high-grade tumors of the brain stem in children. Unfortunately, no cure exists and despite the treatment with radiotherapy the prognosis is dismal and the survival rate for patients remains very low. Primary high-grade tumors grow fast and infiltrate the surrounding tissue with the help of local immune cells, so called microglia. In the healthy brain, microglia support normal brain function and defend the brain during injury or infection. However, cancer cells can reprogram microglia and turn them into tumor-supportive cells, which facilitates the escape from the immune system and promotes the progression of the disease.

The overall aim of our work is to understand the exact contribution of microglia to DIPG occurrence and progression. This knowledge could be used to reverse the pro-tumoral function of microglia and to rekindle their role as guardians of the brain. DIPG tumors are characterised by a very specific gene mutation (known as H3K27M), which affects the expression of multiple genes and biological functions of cells that carry the mutation. More specifically the H3K27M mutation can block the function of the enzyme EZH2. Under normal circumstances EZH2 can induce distinct gene expression patterns in microglia and thereby change their behaviour. Using a cell culture model, we could demonstrate that the pharmaceutical inhibition of EZH2 in microglia reduces their ability to boost the migration and invasive capabilities of DIPG cancer cells. This suggests that the inhibition of EZH2 in microglia could be of interest to combat DIPG tumour progression. To validate this potential therapeutic target, we need to address whether or not microglia within the DIPG tumor carry the H3K27M mutation. This question can only be addressed using brain tissue from DIPG patients, and therefore our request to the Brain UK. 

Project Status: Active

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BRAIN UK Ref: 19/013
Analysis of senescence in pituitary adenomas
Prof. Martinez-Barbera, University College London

Cancers and tumours contain cells that can grow fast (referred to as cancer cells), and others that do not grow at all, which are called senescent cells. Senescent cells have not been studied very much in cancer, however, research from the last 5 years has shown that senescent cells produce and release very potent biological factors that promote and fuel growth of neighbouring cancer cells. These tumour-promoting activities have been shown in a variety of cancers such as liver cancer and leukaemia. More recently, we have demonstrated that senescent cells are important in the development of craniopharyngioma in children, a clinically aggressive brain tumour. Therefore, there is much interest among researchers, clinicians and pharmaceutical companies in assessing whether killing senescent cells can stop or delay tumour/cancer growth and progression. 

The proposed study aims to clarify the role of senescent cells in a tumour called pituitary adenoma. These tumours arise from a hormonal gland that sits at the base of the skull, just underneath the brain. These are usually benign tumours, but in up to 15% of patients the tumours behave aggressively, with rapid growth and resistant to treatments. In this study, we will explore whether using novel drugs, we can kill the senescent cells in pituitary adenomas. If successful, the finding will lead to new clinical trials and novel therapies for the patients.

Project Status: Active

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