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The University of Southampton
BRAIN UK

Lay Summaries of studies supported by BRAIN UK by category: Tumour

BRAIN UK Ref: 13/001
Are neurodegenerative diseases and gliomas inverse comorbidities?
Dr F Roncaroli, Imperial College, London 

The study of the association of different diseases and how they influence each other has proved a promising venue to elucidate the mechanisms underlying several common conditions such as diabetes, cancer and brain degeneration. “Comorbidity” is used when one disease occurs at higher frequency than normal in patients that already have a common condition and “inverse comorbidity” when one disease occurs at a lower than expected frequency in people with a common condition. Patients with degenerative conditions of the brain such as Alzheimer’s disease and Parkinson’s disease often have lower occurrence of cancer than the any other individual of similar age. This evidence led to suggesting that patients with brain degeneration are somehow protected to developing cancer.

The most common and most aggressive brain tumour is called glioblastoma. It occurs at any age but it is vastly more frequent between 50-70 years. Glioblastoma is a killer. Patients with this form of cancer rarely survive longer than 12-14 months form the time the tumour is diagnosed. Cancer cells that constitute glioblastoma can interact with the cells of the normal brain and exploit them to better survive, grow and invade the surroundings.

At the UK Parkinson’s Disease tissue bank at Imperial College, London, we have observed that patients with Parkinson’s disease are unlikely to develop glioblastoma. Such observation was supported by the analysis of death certificates in the UK documenting a much lower than expected occurrence of glioblastoma in patients who died of Parkinson’s and Alzheimer’s disease.

This study aims to understand if the brain affected by degenerative conditions has anything that stops glioblastoma to develop. We have therefore enquired Brain UK to run a survey of the over 36,000 records available for the association between Parkinson’s and Alzheimer’s disease and glioblastoma.

Project Status: Closed

Research Outputs: Abstract

BRAIN UK Ref: 13/002
Investigating inflammation of the normal appearing brain in patients with low-grade glioma
Dr F Roncaroli, Imperial College, London 

A brain tumour can be defined as a mass lesion that is composed mostly of abnormal cells that grow in the brain. The cells can come from the brain itself or from its coverings (primary brain tumours) or from other organs in the body, this latter being defined as secondary or metastatic brain tumours. Primary brain tumours can be benign or malignant while secondary tumours are always aggressive (www.brainstrust.org.uk). There are over a hundred types of primary brain tumour each of which shows different behaviour.

Gliomas are between the commonest types of brain tumour in adults. The way the spread in the normal brain and their growth varies from type to case. Astrocytomas and oligodendrogliomas account for the vast majority of gliomas and they typically invade the surrounding tissue. In order to better define the behaviour of gliomas and guide their treatment, The World Health Organisation has devised a grading system from 1 to 4, grade 4 being those fast growing and therefore most aggressive.

Grade II gliomas are generally defined as low grade (LGG). They account for about 15% of primary brain tumours in adults. Approximately 80% of patients with a LGG present with fits, which progress with time from focal to generalised to eventually become unresponsive to medications. In addition, patients with LGG often develop memory problems and personality changes that impact on the quality of their lives.

In a previous study using imaging techniques, we observed that the brain of patients with LGG is diffusely inflamed compared to normal individuals of the same age. Because inflammation is known to cause damage to the brain, we have decided to study this problem more in depth using tissue supplied by Brain UK.Our aims are to i) prove that results obtained with imaging reflect the reality; ii) understand the mechanism of brain damage caused by inflammation; iii) understand if treatment to reduce inflammation can help to controlling epilepsy and reduce the burden of memory and intellectual problems.

Project Status: Closed

Research Outputs: Presentation x 2

BRAIN UK Ref: 14/004
Pilot study: Expression analysis of candidate transcripts potentially involved in human brain tumourigenesis
Dr. C Barros, Peninsula School of Medicine, Plymouth University 

Within a brain tumour, only a restricted number of cells is able to re-form the whole tumour mass. These so-called brain tumour stem cells (BTSCs) are thought to originate via transformation or de-differentiation from cells of the normal neural stem lineage. Conventional cancer therapies do not effectively destroy BTSCs. The survival of BTSCs may explain the frequent relapse of tumours even after a severe reduction in tumour mass. Therefore, the development of more effective therapies and early diagnostics depend on increased understanding of BTSC properties and mechanisms leading to their development. 

Using the well-established fruit fly central nervous system as a model, we identified novel potential candidate genes involved in the process of development of BTSCs in vivo. About 70% of our candidates have highly conserved matches in humans. Using human tissue requested from the Brain Bank, we are investigating how these newly identified human gene orthologues are expressed in brain tumours compared to normal brain tissue. Out of 24 candidates analysed to date, 21 have been found significantly differentially expressed in tumour versus control samples. This work is an essential stepping-stone to define research directions towards improved characterization of BTSCs and causes of brain tumour formation. 

Project Status: Active

Research Outputs: Grant Application x 2; Presentation x 9; Poster

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BRAIN UK Ref: 14/006
Large scale genetic and epigenetic screen of chordoma
Prof. A Flanagan, University College London 

Chordoma is a rare neoplasm with an incidence of ~1:800,000 of the population. Looking down the microscope chordoma looks like ’notochord’ which is tissue (a rod-like structure running down the spinal axis) and only seen in the embryo up until about 12 weeks of development. Chordoma’s arise where the notochord was originally sited in the embryo/fetus. It is thought that in some individuals the notochord does not disappear and in a few of these individuals the notochord cells grow slowly to form a tumour. The tumour occurs in all age groups and the median period of survival from diagnosis is 7 years. There are few treatment options available. A greater understanding of this disease is needed if we are to improve the lives of those affected. 

Chordoma has been a major focus for the Flanagan research team over the last 8 years (refs. 1-8). The group proposes that there are subtypes of chordoma (for example, those arising in children, those at the base of the skull, those that progress slowly and those that behave aggressively, those that appear to respond to targeted therapies (for example inhibitors of EGFR, cKIT) while others do not - even though this may be for a limited time). To achieve this, the group wishes to study a large number of these rare tumours to understand the differences between chordomas. The aim is to collect a large number of samples and correlate the genetic and epigenetic alterations that occur in this disease, and correlate with clinical outcome.

Project Status: Active

Research Outputs: Publication x 2

DatePublication title
2017 H3F3A (Histone 3.3) G34W Immunohistochemistry: A Reliable Marker Defining Benign and Malignant Giant Cell Tumor of Bone
2017 The Driver Landscape of Sporadic Chordoma
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BRAIN UK Ref: 14/008
An analysis of PPAR expression in human gliomas: its use as a novel diagnostic, prognostic and predictive biomarker
Dr. H Haynes/Dr. K Kurian, University of Bristol 

This research project aims to provide direct translational benefit to patients by investigating a novel biomarker (PPAR: Peroxisome Proliferator-Activated Receptor) which may better predict prognosis and outcome and provide a beneficial treatment target in adult gliomas.

At present, histological grading represents the most reliable, accepted overall indicator for the clinical outcome in adult and paediatric glioma patients. However it is increasingly clear that glial tumours can be subdivided into tumour groups which have fundamentally differing molecular drivers and varying treatment responses. Biomarkers are required so that patients with the same histological diagnosis, tumour location and co-morbidities may receive differing therapies based on the molecular characteristics of their tumours.

We use molecular techniques to study PPAR expression in human glioma samples to establish a relationship with clinical outcome. In collaboration with the University of Edinburgh, we are also analysing how PPAR activating drugs (already in routine clinical use) use may affect the growth and proliferation of brain tumour initiating stem cells without damaging healthy brain. Brain tumour initiating stem cells are responsible for the recurrence and treatment resistance of high grade glial brain tumours. Selectively targeting them in this way therefore has great potential as a novel treatment option to take to early phase clinical trials.

Our preliminary laboratory work has already been presented at national and international conferences and we have on-going collaborations with neurosurgeons and neuro-oncologists as well as clinical geneticists.

Project Status: Closed

Research Outputs: Publication x 3; Grant Application; Abstract x 2; Presentation; Poster x 3

DatePublication title
2017 The Transcription Factor PPARα is Overexpressed and is Associated with a Favourable Prognosis in IDH-wildtype Primary Glioblastoma
2018 Evaluation of the Quality of RNA Extracted from Archival FFPE Glioblastoma and Epilepsy Surgical Samples for Gene Expression Assays
2019 shRNA-mediated PPARα Knockdown in Human Glioma Stem Cells Reduces in Vitro Proliferation and Inhibits Orthotopic Xenograft Tumour Growth

BRAIN UK Ref: 14/009
The role of Numb in the stability and activity of p53 in merlin-deficient tumours schwannoma and meningioma
Dr. S Ammoun, Plymouth University 

Deficiency of the tumour-suppressor protein Merlin leads to the development of tumours in the nervous system such as schwannomas, meningiomas and ependymomas. These tumours can arise spontaneously or as part of a hereditary disease called Neurofibromatosis type 2 (NF2). In NF2, patients develop tumours early in life leading to severe disability and shortened life span. No effective therapies are available and we are trying to find new drug targets by using human tumour cell models (cells artificially grown in the laboratory).

Using our cell model for schwannoma we have previously shown that schwannoma tumour cells multiply quickly when there are high levels of the proteins MDM2 and FAK and degradation of a tumour-suppressor protein called p53. We will now investigate the role of a potentially very important protein called Numb which is known to regulate MDM2 and stabilizes p53 in other cells. Firstly, preparations of human schwannoma and meningioma tissues will be tested for the expression of Numb. Followed, the role of Numb will be investigated using human schwannoma and meningioma tumour cells. As soon we will fully reveal the mechanisms of p53 deregulation in our tumour models we will contact pharmaceutical companies to test new available drugs, firstly in our laboratory model and, if that works, in clinical trials.

Project Status: Closed

BRAIN UK Ref: 14/010
Designing a glioma panel
Miss H Ellis and Dr. K Kurian, University of Bristol

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. 

There are currently several genetic tests that are used to diagnose and identify specific brain tumours. This research project aims to provide direct translational benefit to patients by designing a single test, consisting of a gene panel to identify multiple genomic mutations in several pathways in brain tumour formation.

This may ultimately provide a quicker and more efficient method of diagnosis, and will help clinicians identify appropriate targeted treatments.

Project Status: Closed

Research Outputs: Publication; Publication; Poster x 2

DatePublication title
2015 Current Challenges in Glioblastoma: Intratumour Heterogeneity, Residual Disease, and Models to Predict Disease Recurrence

BRAIN UK Ref: 14/012
Identifying and characterising treatment-resistant subclones in glioblastoma multiforme
Dr L Stead, University of Leeds 

Glioblastoma multiforme (GBM) is the deadliest adult brain cancer, killing almost half of all sufferers within just one year. GBM is thought to be incurable because the tumours are made up of a mixture of cells with different genetic alterations and characteristics that help them survive treatment with radiotherapy and chemotherapy.

My research tests the theory that GBM tumour regrowth (recurrence) results from expansion of groups of treatment-resistant cells present in the original tumour. I plan to test this by using high-throughput sequencing technologies to inspect the different types of cells present in matched original GBM tumours and recurrences following treatment. This will enable me to identify the cells that resisted treatment and then to characterise them, down to the single- cell level, in more detail than ever before.

Identifying and characterising treatment resistant GBM cells will enable us to develop more effective therapies that specifically kill, or inhibit, them.

Project Status: Active

Research Outputs: Publication; Grant Application x 2; Presentation x 2

DatePublication title
2018 Glioma Through the Looking GLASS: Molecular Evolution of Diffuse Gliomas and the Glioma Longitudinal Analysis Consortium
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BRAIN UK Ref: 14/015
The role of Endogenous Retroviral proteins in the development of the tumours of the nervous system and as potential immunotherapy and/or drug targets
Dr. S Ammoun, Plymouth University 

Loss of the tumour-suppressor protein Merlin causes benign tumours of the nervous system. These tumours can occur both spontaneously in people and as a part of the hereditary disease called Neurofibromatosis type 2. Unfortunately, there are no effective drug therapies for these debilitating tumours. 

Endogenous retroviruses are viruses that over millions of years have integrated themselves into the human genome. It is well known that viral protein expression is increased in a range of diseases, and one group of such viruses, called HERVK, are currently being investigated by at least 10 other groups as potential immunotherapy targets for several cancers and HIV infection. 

Using a human cell model to study Merlin-deficient tumours we have found high levels of HERVK proteins and also evidence that HERVK might even be contributing to tumour development. We now need to measure HERVK in actual tumour tissues. Finding high levels will allow us to seek funding for large screens of clinical samples as the next step towards an anti-HERVK drug. Because HERVK proteins are highly expressed in several cancers, we also wish to use our expertise here and measure HERVK expression in malignant brain tumours as a first step towards a wider anti-HERVK based immunotherapy. 

Project Status: Active

Research Output: Grant Application x 3; Abstract x 2

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BRAIN UK Ref: 14/016
Molecular Characterisation of Childhood Craniopharyngioma and Identification and Testing of Novel Drug Targets
Dr. J P Martinez-Barbera (Correspondence with Dr. J Apps), UCL Institute of Child Health 

Dr J P Martinez-Barbera and colleagues at the UCL Institute of Child Health will be undertaking a study into craniopharyngioma. Craniopharyngioma is an aggressive brain tumour in children that causes severe and long-term health problems. The tumour tends to recur after treatment and may require multiple operations. This results in poor quality of life for the patients and sometimes results in death. Currently, the lack of specific treatments and tools to predict patient outcome are barriers in the management of patients with this disease, and these problems can’t be addressed until we gain a better understanding of the biology of Craniopharyngioma tumours. This study aims to look for molecular clues to improve the treatment of this disease.

Project Status: Active

Research Output: Publication x 3; Abstract x 6; Presentation x 2

DatePublication title
2017 MAPK Pathway Control of Stem Cell Proliferation and Differentiation in the Embryonic Pituitary Provides Insights Into the Pathogenesis of Papillary Craniopharyngioma
2018 Tumour Compartment Transcriptomics Demonstrates the Activation of Inflammatory and Odontogenic Programmes in Human Adamantinomatous Craniopharyngioma and Identifies the MAPK/ERK Pathway as a Novel Therapeutic Target
2019 Non-secreting Pituitary Tumours Characterised by Enhanced Expression of YAP/TAZ
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BRAIN UK Ref: 15/001
Intratumoural Heterogeneity in GBM
Miss H Ellis/Dr. K Kurian, University of Bristol 

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

Research Outputs: Publication

DatePublication title
2015 Current Challenges in Glioblastoma: Intratumour Heterogeneity, Residual Disease, and Models to Predict Disease Recurrence
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BRAIN UK Ref: 15/005
Dissecting the origins of central nervous system tumours exhibiting neuromesodermal differentiation
Dr. A Tsakiridis, University of Edinburgh 

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: Closed

Research Outputs: Grant Application

BRAIN UK Ref: 15/006
Identifying Circulating Tumour Cells in the Blood: An Analysis of their Diagnostic and Prognostic Significance in Correlation with Biopsy Findings
Miss Williams/ Dr. K Kurian, University of Bristol 

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

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BRAIN UK Ref: 15/009
Assessment of expression and potential role of prmt5 and its upstream and downstream regulators in paediatric tumours
Dr Z Melegh, University of Bristol 

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, mededlloblastomas 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 mededlloblastoma 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 mededlloblastoma.

Project Status: Active

Research Outputs: Poster

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BRAIN UK Ref: 15/011
A pilot study analyzing the effect of driver mutations on the (phospho)proteome and microenvironment of meningiomas
Prof. O Hanemann), Plymouth University 

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

Research Outputs: Abstract x 3; Presentation x 12

Date   Publication title
 2018  Proteomic analysis discovers the differential expression of novel proteins and phosphoproteins in meningioma including NEK9, HK2 and SET and deregulation of RNA metabolism
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BRAIN UK Ref: 15/012
Investigating the role of macrophages in schwannoma tumours of the PNS
Prof. D Parkinson, Plymouth University; Dr S Aditya, Plymouth Hospital

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: Closed

Research Outputs: Abstract

BRAIN UK Ref: 15/015
Examining the genomic landscape of rare brain tumour types
Dr Hayley Ellis, University of Bristol

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 

Research Outputs: Publication

DatePublication title
2017 DNA Methylation-Based Classification and Grading System for Meningioma: A Multicentre, Retrospective Analysis
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BRAIN UK Ref: 15/016
Molecular neuropathology of posterior pituitary/TTF-1-positive neoplasms
Dr Olaf Ansorge, Oxford University

Tumours arising at the base of the brain can interfere with hormonal function and vision. We want to describe the features of a rare group of such tumours that share a distinct marker, called TTF- 1, which suggests that they may have a common origin. Specifically, our study aims to define the genetic relationship between the tumours that have this unifying molecule – do they share a genetic make-up, or are there distinctive features? Currently, treatment of these tumours relies on surgery; no specific drug is available. We hope our study will (1) help to define better these tumours and as a result (2) point to genetic events that drive their make-up, which may offer new targets for therapy. The tumours are rare; this is why we request help from Brain UK, so we can study as many samples as possible. The results will be published.

Project Status: Active

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BRAIN UK Ref: 15/017
PPAR expression in glioblastoma as a putative prognostic biomarker
Dr. H Haynes/Dr. K Kurian, University of Bristol

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: Closed

Research Outputs: See 14/008

BRAIN UK Ref: 16/001
Investigation of the role of the c-MET proto-oncogene and the PI3K/AKT/mTOR pathway in brain metastasis.
Prof. Carlo Palmieri, University of Liverpool

Breast cancer (BC) is the second most common cancer diagnosed worldwide. The most severe form of BC occurs when it spreads (metastasis) from the breast tissue to other regions of the body such as liver, lung, bone and brain. Breast cancer brain metastasis (BCBM) is high despite the performance of current treatments and unfortunately, is incurable. Therefore, it is necessary to try and understand the metastatic machinery that directs breast cancer cells to the brain and helps them establish BCBM. The machinery (human genome) that controls our cells, is composed of different tools (known as genes and proteins) that communicate and regulate each other forming a pathway. Any changes on these tools can affect their interaction and alter their pathway leading to cancer development and metastasis. This project aims to investigate further how these changes lead to communication problems between genes and pathways in brain metastasis by using a large number of BCBM cases. This knowledge will helps us to improve treatment selection and facilitate the development of new drugs.

Project Status: Active

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BRAIN UK Ref: 16/002
Multi-platform analysis of TSC Subependymal Giant Cell Astrocytoma (SEGA) to identify novel therapeutic approaches.
Dr Eleonora Aronica/Dr Angelika Mühlebner, Academic Medical Centre, Amsterdam

Tuberous Sclerosis Complex (TSC). TSC is a genetic disease which causes multiple tumours within the body. Heart, brain, kidney, skin and lung can be affected. Subependymal giant cell astrocytoma (SEGA) are benign tumours. These grow slowly but constantly in brains of the patients. In children they are one of the more common causes of complications associated with the disease. This leads to brain swelling (increased intracranial pressure) and all associated risks. The treatment of the tumour usually means surgery or medication with so-called mTOR-inhibitors. These are specific types of medications targeting the mTOR complex which is the main affected protein complex in TSC. However, little is known about how these tumours grow and why some of them are more responsive to medication than others. Therefore, we use a battery of modern techniques to gain insights in the development of these tumours and unravel novel therapy strategies.

Project Status: Active

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BRAIN UK Ref: 16/007
INSTINCT
Dr T Jacques, University College London Institute of Child Health 

Background:
Despite recent treatment advances ‘high-risk’ paediatric brain tumours (HR-PBTs) remain the leading cause of deaths from cancer in childhood. Advances in biological understanding, and their translation into effective therapies, will be essential to improve outcomes for these children, and coordinated national/international strategies will be required to achieve this.

The INSTINCT programme brings together UCL Institute of Child Health, Newcastle University Northern Institute for Cancer Research and the Institute of Cancer Research, each of which already play international leading roles in paediatric brain tumour research.

What does INSTINCT aim to achieve?
INSTINCT specifically aims to bridge the gap between biological discovery and clinical practice through using state-of–the-art biological investigations to improve the outlook for children with HR-PBTs.
BRAIN UK will support and facilitate the use of archival hospital brain tumour samples for molecular sequencing.
Through co-ordinated research and clinical networks between our centres, our research will:

Advance knowledge of brain tumour biology
• Ensure improved diagnosis
• Lead to future clinical trials
• Enable new effective treatments to be developed
• Increase the profile of brain tumour research to public, patient, academic and funding stakeholders
• Train researchers and clinicians of the future

Project Status: Active

Research Outputs: Publication; Grant Application; Poster x 5

DatePublication title
2018 CNS Embryonal Tumours: WHO 2016 and Beyond
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BRAIN UK Ref: 16/008
Developing a Biomarker for Spinal Lipoma 
Dr V. Jones, University College London Institute of Child Health 

Lumbosacral spinal lipomas (LSL) are part of the spectrum of spina bifida. In “open” spina bifida the developing spinal cord does not close properly and is not covered with skin. LSLs also form when the spinal cord does not form properly, however, the skin does form over the defect, so LSLs are considered to be “closed” spina bifida. Folate supplements early in pregnancy reduces the risk of open spina bifida but not LSLs - this suggests there is a very different underlying mechanism.

Recent assessment of LSL tissue samples show that although they are called lipomas (this normally refers to a collection of fat cells), in reality there is a diverse range of different cell types present. This has led us to propose a mechanism by which LSLs might develop. There is a group of cells that form with the developing spinal cord called neural crest cells. Recent research has shown that neural crest cells are capable of forming a wide range of different cell types including the fat cells found in LSLs.

In this study we will assess archived samples taken from children at time of surgical resection of their LSLs. We will assess these samples to see if there are any markers of neural crest cells present. If there are this will help guide further research, help us develop a model and hopefully find a way to prevent this disease.

Project Status: Active

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BRAIN UK Ref: 16/011
Identification of novel therapeutic targets in malignant peripheral nerve sheath tumours (MPNST)
Prof. O Hanemann, Plymouth University 

Malignant peripheral nerve sheath tumours (MPNST) can occur at numerous sites in the body and form within the outer layer of nerves. MPNSTs are associated with poor patient survival and are more common in a group of patients with a genetic condition called Neurofibromatosis type 1. These patients are missing an important protein, Neurofibromin 1, which normally prevents tumour growth along nerves. When Neurofibromin 1 is absent, it leads to an increase or decrease in many other proteins, helping the tumour to grow and survive. We are interested in finding new treatments for patients who have an MPNST that is missing Neurofibromin 1. We will look at a number of proteins that are increased in other tumours and determine if they are increased in MPNST tumours. If they are, we will use a drug to stop these proteins from working and see if there are any changes in tumour growth. In the future these drugs could be used to treat patients instead of invasive surgery and they may be able to improve patient survival.

Project status: Closed

BRAIN UK Ref: 16/015
The development of a molecular methodology for improved detection of Isocitrate Dehydrogenase mutations in diffuse gliomas.
Dr R Ganderton, University Hospital Southampton NHS Foundation Trust

Changes in our DNA are often found in cancer. In the hospital laboratory we can set up tests to look for these changes, to help diagnose and treat cancer. In a brain cancer called glioma, we need to find some better tests to help with getting the diagnosis right. We want to try a new method called ‘digital PCR’ that should help us give a more accurate way of looking for a mutation in the gene IDH1, which is very common in this cancer. We will compare the method with the way the test is done now, looking at cells down a microscope, to see if we can get a better test. We also want to add in some ‘DNA sequencing’ to try and pick up rarer IDH mutations that can be found in glioma; currently our hospital can’t offer this extra service. These extra tests will mean we can help the doctors to make a more accurate diagnosis of the disease. This should in turn make sure the patients get the most appropriate treatment.

Project Status: Closed

Research Outputs: Poster

BRAIN UK Ref: 16/017
Molecular pathology of infant gliomas
Dr Matthew Clarke, Institute of Cancer Research UK

The diagnosis of a high-grade glioma (a type of brain tumour) in a child has a dismal prognosis ranging from a 2 year survival of <10 – 30% depending on where the tumour is located within the brain. However, a small group of tumours that occur in infants tend to have a better prognosis than those occurring in older children. And we want to try and find out why. There is a great need to study the molecular biology of these tumours to better understand how they grow, develop and identify potential targets for treatment. We are gathering samples of different brain tumours from children who are aged less than 4 years old. We are using microscopes to assess the different features of the tumour cells, and we are performing various molecular experiments and tests on these samples to try and find the different genetic abnormalities that occur within the cancer cells. Once these are identified, we can try and design different drugs that can be used to try and stop the cancer from growing and help to improve the survival of the children diagnosed with these tumours.

Project status: Active

Research Outputs: Presentation x 8

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BRAIN UK Ref: 16/018
Determining the cell of origin of primary central nervous system lymphomas 
Dr Lilla Reiniger, Semmelweis University, Hungary

Primary central nervous system lymphoma (PCNSL) is a rare cancer with a generally poor outcome and with very limited therapeutic choices resulting in a short patient survival (the median overall survival ranges from 2 to 4 years). Despite intensive research activities, our understanding of the disease remains obscure; moreover, most of the data has emerged from relatively small studies. In this project we will investigate the origin of tumour cells in a relatively large cohort of PCNSL and correlate the results to clinical data and the frequency of mutations of different genes involved in development of PCNSL. We will use different modern molecular and immunohistochemical techniques. Our research will lead to better understanding of PCNSL, and ultimately will allow us to offer novel prognostic biomarkers and potential therapeutic targets to the patients.

Project Status: Closed

Research Outputs: Abstract; Presentation

Date Publication title
 2019  Molecular Subtypes and Genomic Profile of Primary Central Nervous System Lymphoma.

BRAIN UK Ref: 17/002
Identification of novel therapeutic targets and/or predictive biomarkers in brain gliomas
Prof Ji-Liang Li, Plymouth University

Brain gliomas, a class of brain tumours, can be low grade (slow growing) or, more commonly, high grade (fast growing). About half of low grade gliomas progress to a higher grade of tumour. Compared to other tumours, current knowledge about brain tumour is still very limited.

We know that a type of biological signalling between cells, called Notch signalling, starts the binding of a protein on one cell to another protein on a neighbouring cell and activates cell to cell signals or communication that determines the cells fate. This signalling plays an important role in human development such as unborn baby development in pregnant woman. In this study, we will investigate if some important molecules involved in either Notch signalling or other signal pathways controlling cell growth could control glioma growth and tumour development as well as tumour response to drug therapy. We aim to develop new treatments or identify if there is a genetic test that could indicate if a treatment would work or expected patient outcome.

Project status: Active

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BRAIN UK Ref: 17/003
Molecular Pathology of Paediatric Gliomatosis Cerebri
Dr Chris Jones, Institute of Cancer Research 

Gliomatosis cerebri is a very rare type of brain cancer with a very poor outcome. A child diagnosed with gliomatosis cerebri will survive on average 17 months. It is not a solid tumour; cancerous cells spread diffusely throughout the brain in a threadlike fashion. Lack of a solid mass makes surgical removal difficult, leaving radiotherapy and/or chemotherapy as the only options. The rarity of this disease means it is difficult to study as obtaining a wide range of samples is a challenge, especially from children.
We do know however that gliomatosis cerebri in children differs, at the molecular level, to adults and needs to be treated as such.
Since no distinct genetic mutations have so far been discovered, the World Heath Organisation 2016 update has declassified gliomatosis cerebri as a separate type of brain cancer. Nonetheless, some features of gliomatosis crebri are still unexplained and the addition of samples from BrainUK will help us shed light on it. This will be achieved by utilising various molecular analysis techniques to identify genetic mutations that set it apart from other types of brain cancer. This information will be vital in identifying drug targets to improve the survival statistics for these children.

Project status: Closed

Research Outputs: Presentation

BRAIN UK Ref: 17/004
Single-cell phenotyping technique applied to glioblastoma tumour samples as compared to normal brain tissue.
Dr Thomas Millner, Queen Mary University of London

Malignant gliomas are highly invasive primary brain tumours. Glioblastoma is the most common of these tumours and is often resistant to treatment as it cannot be completely removed with surgery, and conventional anticancer treatments, such as chemo- and radio-therapy, have limited efficacy.

I study the epigenetics of glioblastoma. Epigenetics describes the biological mechanisms that switch genes on and off. All the cells in our bodies have the same genes, but what makes a brain cell different from a skin cell is which of these genes are turned on. Glioblastoma develops from normal neural stem cells. Within these normal cells there have been both genetic mutations and problems with the epigenetic machinery, which leads to the development of brain tumours. I am trying to shed light on some of these problems. 

This project will use state of the art tissue clearing techniques to look at brain tumour cells in fine detail and in 3D within their native environment. We want to do this to try and better understand the ways some of these epigenetic mechanisms contribute to brain tumour development, with the final aim to develop more effective treatments for patients who suffer from this terrible disease. 

Project status: Closed

Research Outputs: Abstract; Presentation

BRAIN UK Ref: 17/005
Characterization and analysis of the brain tumour perivascular niche 
Dr Georgia Mavria, University of Leeds

Glioblastoma remains one of the deadliest cancers regardless of the current standard therapy, which is surgery to remove the tumour commonly combined with radiotherapy and chemotherapy. Unfortunately, remaining cancer cells escape treatment and the tumour regrows making the disease highly resistant to treatment. The formation of blood vessels is crucial for cancer growth, and at the same time the blood vessels also provide an environment that protects the cancer cells that resist standard therapies. Several abnormalities have been described in the blood vessels of glioblastoma compared to blood vessels in the healthy body, these are thought to contribute to the protection of the cancer cells. However, how abundant these abnormalities are unknown and little is known about how such abnormal blood vessels arise at the cellular and molecular level.

In this study, we are going to characterize paired early and recurrent glioblastoma patient samples for different blood vessel structures. Our preliminary studies using a small number of patient samples show that there are marked differences between primary tumours, and more aggressive tumours that reappeared after treatment (recurrent). We will work to use the characterization of blood vessels as a marker to more precisely determine the stage of disease and ultimately whether reversing blood vessel abnormality can work as a strategy for the development of new treatments.

Project status: Active

Research Outputs: Grant Application; Abstract

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BRAIN UK Ref: 17/007
Research and Innovation for Paediatric Low Grade Brain Tumours-Incorporating the SIGNAL and Everest (formerly PINNACLE) multicentre studies
Dr Tom Jacques, University College London/ Great Ormond Street Hospital for Children NHS Foundation Trust

Paediatric low-grade brain tumours are a large group of tumours with similar origins and behaviour. They are the most common brain tumours in children, accounting for about 1 in 3 cases. While most children with these tumours will survive, some children still die and many survivors suffer from long-term health problems as a result of the tumour or as side effects from the treatment they receive. Recent discoveries have shown that this group of tumours is more complex than previously thought. This has highlighted the need for accurate diagnosis, which is necessary to plan treatment accordingly and reduce the harmful effects experienced by patients. In order to achieve this we must urgently improve our understanding of the biology of these tumours (how and why they develop) and translate that knowledge into the clinic to benefit patients and their families.

Our research aims are:
1.     To identify the types of brain cells that these tumours develop from, and the changes that cause them to become cancerous. This will help us to more accurately diagnose patients, find new targets for treatment, and identify signs that indicate a tumour will behave aggressively. By ensuring early and precise diagnosis we can tailor treatments to give each individual patient the best treatment for their specific tumour.
2.     To investigate how tumour cells interact with their surroundings, and whether the body’s immune system can be activated to attack the tumour cells as a new form of treatment (“immunotherapy”).
3.     To coordinate an international clinical trial to compare new precisely-targeted therapies with standard treatments. We will compare survival rates and also measure (and hopefully reduce) the long-term impacts of these tumours on brain function and quality of life in survivors.

Project Status: Active

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BRAIN UK Ref: 17/008
Analysis of paediatric brain tissue by RAMAN imaging technology 
Prof Geraint Thomas, University College London

Brain tumours are the commonest solid tumour found in children and the commonest tumour to kill children. Long-term disability is relatively frequent amongst survivors, reflecting in part the impact of intensive treatment on children’s brains.

There are multiple different types of brain tumour and each type responds to different kinds of treatment. Therefore a major challenge is to be able to distinguish which kind of tumour a child has so we can adapt their treatment. Children who are most likely to respond can be offered the most appropriate treatment. Furthermore, children whose tumour is unlikely to respond to a particular treatment, can avoid the toxic effects of that treatment.

We are investigating a novel way to test the brain tumour after it has been removed from the child’s brain. The technique is called Raman microspectroscopy and we hope that it will allow us to rapidly determine the type of tumour. Our aims are to use it in routine tumour diagnosis.

Project Status: Closed

BRAIN UK Ref: 17/012
Defining changes in the tumour microenvironment of melanoma brain metastases following anti-PD-1 and anti-CTLA-4 antibody therapy
Dr Mihaela Lorger, University of Leeds

Melanoma is a type of skin cancer that can spread to other parts of the body. Once melanoma has spread, it is known as metastatic melanoma. In recent years new drugs have been approved for the treatment of metastatic melanoma. These drugs inhibit the molecules called PD-1 and CTLA-4 that are present on a subpopulation of white blood cells called T lymphocytes. Inhibition of PD-1 and CTLA-4 helps the immune system to attack the cancer. This therapy significantly extends lives of melanoma patients and combined inhibition of PD-1 and CTLA-4 results in complete responses in 11.5 % of the patients. In order to develop approaches that further improve efficiency of this therapy, it is important to gain a better understanding of how these drugs work. Our goal is to understand how the efficiency of PD-1 and CTLA-4 blockade could be improved in the brain, to which cancer spreads in up to 60% of metastatic melanoma patients. To this end we plan to analyse brain tumour tissue of melanoma patients that received therapies targeting PD-1 and/or CTLA-4. This is expected to provide a better insight into which immune cells contribute to successful therapy and what is required for their entry into brain tumours.

Project Status: Active

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BRAIN UK Ref: 17/013
Establishing microglial phenotype in glioblastoma as a potential target for therapeutic intervention
Prof Delphine Boche, University of Southampton

Glioblastoma is the most frequent brain tumour in adult.  Despite the current treatment, the diagnosis of brain tumour is associated with a short survival time of around 1 year.  Brain tumour is composed of a mix of inflammatory and tumour cells. The current thinking is that the inflammatory cells are participating in the growth of the tumour instead of recognising the tumour cells as a pathogen.  With this project, we wish to characterise the inflammatory cells and their relationship with the tumour cells.  The information collected will be used to develop a laboratory model similar to the human brain tumour allowing manipulation of the inflammatory cells or the tumour cells to identify a target for treatment.

Project Status: Active

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BRAIN UK Ref: 18/001
Role of c-Myc in choroid plexus tumours (Revised application to previous applications BRAIN UK Ref: 13/003 and 15/007) 
Dr Ashirwad Merve, Blizard Institute, Barts and The London School of Medicine and Dentistry

Choroid plexus tumours (CPT) are rare brain tumour that mostly occur in children. Majority of them are benign, and are treated mainly by surgery, with a risk of surgical complications in some children. Moreover, not all tumours can be completely removed. A proportion of them can recur or spread to other parts of brain or spinal cord, and a minority of them can also progress to become malignant. Due to its rarity, there is currently limited knowledge about the genetic changes that lead to development and progression of these tumours.

In our study, we are interested in the effects of a gene called c-Myc, which is well known to be abnormal in various malignancies. We are interested in this gene because, we incidentally observed CPT developing in a high proportion of mouse models, which were genetically engineered to have increased expression of c-Myc. We also found that a third of the human CPTs express high levels of c-Myc. Our preliminary results suggests that c-Myc contributes towards development of CPT by altering the inflammation system in the choroid plexus tissue. This is a new finding, and we hypothesise that, CPT with high c-MYC expression, responds to anti-inflammatory drug treatment. 

If our hypothesis is proven, then it would be basis for further clinical trials with anti-inflammatory treatment. This would be ground to test if the patients with CPTs could be treated with drugs/medicines only, hence avoiding surgery and its adverse effects on the developing brain of the children.  

Project Status: Closed

Research Outputs: Abstract x 7; Presentation x 3; Prize

 DatePublication title
2019 c-MYC overexpression induces choroid plexus papillomas through a T-cell mediated inflammatory mechanism

BRAIN UK Ref: 18/003
Validation of prognostic markers and therapeutic targets in a large cohort of primary versus recurrent glioblastomas
Dr Nelofer Syed, Imperial College London

Glioblastoma multiforme (GBM) is the most common and aggressive primary brain tumour. Most cases result in the tumour coming back (recurrence) which has driven a need to characterise the genetic changes associated with tumour recurrence to identify new and more effective treatments.

In our lab we have undertaken an initial study of the genetic profile of 10 tissue samples from primary and recurrent adult GBMs.  We have used RNA-sequencing, a genome-wide sequencing technique that can reveal mutations in genes as well as changes in their activity/expression. Our results have identified several genes that may be responsible for tumour regrowth and resistance to standard therapy.

This study aims to extend our initial study to a wider number of samples and increase our understanding and characterising of the genes involved in tumour regrowth and resistance.  This will inform the development of novel treatments.

Project Status: Active

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BRAIN UK Ref: 18/004
Contribution of soft tissue tumours to DNA methylation-based sarcoma classifier
Prof Andreas Von Deimling, University Heidelberg and Prof Sebastian Brandner, University College London

This study will provide tissue which will be used to build a computer based algorithm that can better diagnose tumours arising from the soft tissues, such as connective tissue, muscle, bone, and cartilage.

This algorithm will work in a similar way as that recently published for brain tumours. 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 University College London Hospital (UCLH)/National Hospital for Neurology and Neurosurgery (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 soft tissue tumours. Soft tissue tumours are frequently found in the vicinity of the spine, and are operated by our spinal surgeons.

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 the algorithm has made a different diagnosis, which has significantly changed the treatment of some of our patients. It is predicted that also sarcoma classifier will significantly improve the clinical management of patients with soft tissue tumours.

Project Status: Closed

BRAIN UK Ref: 18/005
An Investigation of the Clinical Utility of Genetic and Epigenetic Profiling in Glioma
Dr Rosalind Ganderton, University Hospital Southampton

Genetic tests are becoming increasing important in how we diagnose and treat brain cancer. Currently, tests are done one at a time, using different methods, and it is not possible to do every single test that might be of relevance. New genetic technologies mean that we can now look at everyone’s entire DNA sequence at a cost a little more than a current single genetic test. Having all this genetic information is helpful in diagnosing the patients’ disease and what treatment would be best for them. A number of our patients have volunteered for their DNA to be sequenced in this way, as part of the 100,000 genomes project. We would like to look at this data and relate it to another big genetic test called ‘genome-wide methylation analysis’. We have a rare opportunity to link all the scientific data together with very good clinical information about the patient, their disease and how they are doing now. We want to see if this combined information can be used to provide a more accurate diagnosis and maybe give better information about the long-term outcome for patients. It is also possible it could be used to guide a more personalized therapy programme for patients. Additionally, if all of the tests could be done together, it could produce a more streamline cost-effective Laboratory service, at a time when there is work pressure in all parts of the NHS.

Project Status: Closed

Research Outputs: Poster

BRAIN UK Ref: 18/006
Study of Biological Abnormalities in Meningiomas
Mr Thomas Santarius, Cambridge University Hospitals

Lay Summary not yet available. 

Project Status: Active

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BRAIN UK Ref: 18/008
Characterising the role of chromatin regulator EZH2 in glioblastoma
Dr Paola Scaffidi, The Francis Crick Institute, London 

Glioblastoma is the most common form of brain cancer, affecting over 2000 people every year in the UK. Despite large amounts of research, few drugs exist which can consistently treat this cancer. Recent work has shown that a protein called EZH2 is extremely important in many cancer types. As a result, drugs have been made which switch off the EZH2 protein, causing tumours to shrink. We want to understand whether the EZH2 protein is also important in glioblastoma. Furthermore, we would like to know whether switching off the EZH2 protein with drugs could be an effective treatment. Excitingly, using laboratory models of glioblastoma, we have previously shown that the EZH2 protein is needed to make the cells of this tumour grow. To understand whether this is also the case in real tumours, we will use samples from the BRAIN UK biobank to confirm the importance of the EZH2 protein. This confirmation will be crucial in letting us know whether drugs targeting the EZH2 protein could be used to treat patients with glioblastoma in the future.

Project Status: Closed

 DatePublication title
 2019  Redistribution of EZH2 promotes malignant phenotypes by rewiring developmental programmes

BRAIN UK Ref: 18/009
Dissecting GBM invasion
Professor Simona Parrinello, Cancer Institute, UCL 

Glioblastoma (GBM) is the most common and aggressive type of primary brain tumour, with 2,200 new cases diagnosed each year in the UK. Despite available therapies, the median survival of GBM patients remains at less than 15 months and 5-year survival rate at less than 5%. There is therefore an urgent medical need to increase basic and translational research in this devastating disease.

A major reason for this dismal prognosis is the invasion of GBM cells into the normal brain.Invasion is a major clinical challenge because it prevents complete surgical resection and hinders radiotherapy, resulting in tumour regrowth from residual invasive cells. GBM cells invade into the brain by hijacking pre-existing structures such as blood vessels and white matter tracts (WMT). WMT infiltration is particularly common, yet despite its importance, the molecular basis of this type of invasion remains almost entirely unknown.

We have identified molecules that are increased in white matter invading cells in mouse models and would now like to understand how relevant these are to the human disease.

These studies have the potential to identify novel markers and therapeutic targets to block GBM invasion and recurrence.

Project Status: Active

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BRAIN UK Ref: 18/013
Proteomic analysis of primary and recurrent glioblastoma – a pilot study
Professor Silvia Marino, Queen Mary University of London

Glioblastoma is the most aggressive type of brain tumour.  Treatment is rarely successful and new ones are urgently required. 

Control of how a cell works, including glioblastoma cells, involves information passing from the genes (DNA) to an intermediate step (RNA) and then finally into protein.  It is the proteins that are responsible for doing much of the work in a cell.  The process is tightly controlled with checks at each stage.  This means that the presence of a particular gene/RNA will not automatically lead to the presence of that protein.  Most medicines, including cancer medicines, act by stopping specific proteins from working, rather than affecting the gene/RNA.  Therefore, knowing which proteins are present in glioblastoma cells is key to developing new medicines.  However, previous studies have only looked at which genes/RNA are present.

Until recently, it was costly and difficult to look at the proteins present in a cell in great depth.  However, the technology has now improved such that it is possible with a technique called mass spectrometry.  This pilot study will be used to find the best way to extract DNA, RNA and protein from glioblastoma samples and to show that mass spectrometry can be used to look at the proteins present.  This will be done on five samples which have been stored in two different ways (ten samples in total).  The findings will be used for a grant application to Cancer Research UK to fund a larger project using mass spectrometry to identify the proteins present in 100 glioblastoma samples.  It is hoped that this project will lead to new medicines for the treatment of glioblastoma.

Project Status: Closed

BRAIN UK Ref: 18/014
Whole Exome Sequencing of Primary Diffuse Large B Cell Lymphoma of the Central Nervous System
Dr Yuening Zhang, Southmead Hospital, Bristol

Brain lymphomas are aggressive cancers. They can have an extremely poor prognosis for patients. There is limited information about how they arise, why they behave in such a malignant fashion and why they don’t respond well to current treatments. We hope to find out more about the biology of lymphomas and want to find some clues about how they may be better treated. We will be using biopsy tissue of a number of brain lymphomas and performing DNA sequencing. This will help us find any significant mutations in important areas of DNA. These areas are likely to hold important information that should help to explain the behaviour of the tumour and may be targets for drug therapy. By performing this test on a number of brain lymphoma samples, we will be better able to see any recurring mutations in brain lymphomas, and compare these to the mutations seen in lymphomas in other parts of the body. This will show us what differences there might be. We hope that this study will help in improving future diagnosis and treatment for this devastating disease.

Project Status: Active

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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

 DatePublication title
2019  Methylation array profiling of adult brain tumours: diagnostic outcomes in a large, single centre.
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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: 19/009
Characterisation of the Glioblastoma Immune Microenvironment
Dr Paul Mulholland, University College London Hospital

Glioblastoma (GBM) is the most common form of brain cancer in adults. If treated, the  average survival in patients with this diagnosis is 14 months. So there is an urgent clinical need for new and improved treatments. Glioblastoma cells exploit the brain’s internal safety systems which means the cancer cells evade detection. This means that treatments tend to fail. The biology of brain tumours, their environment and how tumour cells interact with it are poorly understood. The tumour’s environment contain cells which are part of the immune system and it is thought that these cells protect the tumour from the different treatments and support tumour growth. Our project wants to find out which cells are present in the tumour’s environment and find out which genes are active and which ones are switched off. We will be performing this analysis using stored tumour tissues. Specifically we will be staining the tissues with fluorescent dyes. This will identify the different cells present. We will also be measuring the activity of genes related to the immune system and link them with the clinical data to uncover molecular pathways conferring resistance or sensitivity to a particular treatment.  This body of work will give us new insight into the communication between cancer cells and normal cells within the brain.

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: 19/012
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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