Image - Adam Dealey Image - The Adam Dealey Foundation for Ewing Sarcoma
Working in partnership with www.bonecancerresearch.org.uk (Registered Charity No. 1113276)

UKCCSG (The United Kingdom Children's Cancer Study Group)
& Adam Dealey Foundation Partnership

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Doctor Sue Ablett and the search for a cure:

We a fortunate at The Adam Dealey Foundation to have Doctor Sue Ablett heading up the team into research of Childhood Cancers. Dr Ablett in conjunction with many doctors and research scientists around the world are constantly searching for ways to ease the suffering of children having chemotherapy and other forms of treatment. We hope as we move along to show just a fraction of the work Dr Ablett and her team are working on at present (for in-depth information regarding the UKCCSG please click logo above).

The body UKCCSG makeup:

The United Kingdom Children's Cancer Study Group (UKCCSG) aims to improve the management of children with cancer and to advance the knowledge and study of childhood malignancy. The Group has over 400 members, working in 22 specialized Paediatric Oncology centres throughout the British Isles, and including about 50 overseas members. Membership of the Group includes all disciplines involved in the treatment of children with cancer. The activities for the Group are coordinated through the UKCCSG Data Centre in Leicester.

Tumours of the Ewing Sarcoma family: (extract)

Both tumours of the Ewing sarcoma family and Neuroblastoma are solid tumours of neural origin, thought to arise following arrest of cells and commitment to an abnormal lineage during development. Since some growth factors and their receptors have a critical role in the regulation of neural development, we have explored the hypothesis that these factors regulate the behaviour of these tumours and may provide novel mechanisms for the modulation of their behaviour. This may ultimately lead to the identification of new targets for therapeutic intervention.

Basic fibroblast growth factor (bFGF):

Image - Basic fibroblast growth factor (bFGF)

Basic fibroblast growth factor (bFGF) has a critical role in neuronal cell development, and has been implicated in the process of neoplastic transformation by increasing growth and angiogenesis in many tumour types. However, we have previously shown that whilst treatment of neuroblastoma cells with bFGF increases cell growth and may be involved in malignant progression, treatment of Ewing Sarcoma cells with this growth factor causes them to die. This is a very exciting observation and may lead to the identification of novel strategies to kill Ewing Sarcoma cells. The aim of studies funded by the Adam Dealey Foundation for Ewing Sarcoma is to investigate the mechanism of bFGF-induced cell death in Ewing Sarcoma.

bFGF:

bFGF is a ubiquitously expressed growth factor which effects a change in cell behaviour via the high affinity FGF receptors (FGFR). There are four high affinity receptors (of which there are many variants) shown to be expressed in a cell and tissue specific manner, thus allowing cell response. The FGF receptor profile on the Ewing Sarcoma cells therefore provide a mechanism by which bFGF may induce cell death.

Image - Effect of bFGF on Ewing's cell growth

Apoptotic necrotic and mitotic cell populations in RD-ES cells treated with bFGF.

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bFGF-induced cell death. The cells are vacuolated and breaking up as the bFGF kills them.

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Effect of bFGF on Ewing's cell growth - Concentration of bFGF (ng/ml).

Molecular Techniques:

Using molecular techniques we have identified all four high affinity FGF receptors and the common slice variants that have been described in a panel of Ewing Sarcoma an neuroblastoma cells. However, we also identified a novel variant of FGFE-3 in the Ewing Sarcoma cells, that was not found in the neuroblastoma cells and has not previously been described. This variant was also present in a breast carcinoma cell line in which bFGF also induces cell death. This novel receptor variant is expressed in all the Ewing Sarcoma derived cell lines we have examined, and more recently we have also shown it is also expressed in primary tumour material. Interestingly we have not found the receptor in any normal tissues. This suggests the receptor is specifically expressed in tumour material and tumour cell lines, which is very exciting as it may be a potential tumour specific target for therapeutics intervention.

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bFGF -induced cell death - Targets to modulate behaviour of Ewing's Sarcoma Prognostic factors.

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Mechanism of bFGF-induced cell death.

Sequence analysis:

Sequence analysis of the receptor has shown it to have features consistent with a receptor that is constitutively activated. Constitutive activation of FGFR-3 has been implicated in various skeletal dysplasias, all of which involve premature cell maturation or death in neural crest derived structures. This would support our hypothesis that this tumour specific FGFR-3 variant may be involved in bFGF-induced cell death. We are currently investigating this novel receptor further, and hope to perform functional studies to clarify it's role in the induction of cell death by bFGF.

This work has been carried out by Dr. Lisa Sturla and Dr. Susan Burchill in the Candlelighter's Research Laboratory, ICRF Cancer Medical Research Unit.

Dr Sturla is funded by the Adam Dealey Foundation for Ewing Sarcoma.

Progress in Understanding the Biology of Ewing's Tumours:

1). Doctors and scientists are continuing to make advances in understanding the ways in which cancers such as Ewing's tumours develop. We know that cancers arise as a result of abnormalities in the genes that control the way a cell behaves. Increased understanding of how faulty genes contribute to the development of cancer offers new ways for doctors to diagnose, monitor and treat a whole range of tumours, including Ewing's tumours.

2). We are studying the genes that are abnormal in Ewing's tumours by looking at the structures in the cell, known as chromosomes, that contain the genes. Until recently, it has been difficult to identify individual chromosomes, although we are now able to do this by using new techniques, partly developed in Cambridge, in which each of the chromosomes is 'painted' a unique colour, allowing us to recognize each one and to identify abnormalities (see image below).

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Using 'painting approach to identify abnormalities in the chromosomes, Cambridge University.

3). Using this 'painting approach, we have identified a large number of abnormalities of the chromosomes in Ewing's tumour cells. Importantly, certain chromosomes appear to be abnormal in cells from many different Ewing's tumours. This suggests that these common chromosomes disorders may be involved in the development or progression of the tumours. We will be examining selected chromosomes in more detail during the forthcoming year, with a view to ultimately identifying genes involved in the abnormalities that we have detected.

4). Our group has been able to make excellent progress over the last year. We have recently submitted a scientific paper for publication and are preparing two more. We have made numerous presentations at medical and scientific meetings, both notionally and internationally. We would like to record our gratitude to the Adam Dealey Fund, which has generously supported our work on Ewing's tumours.

Nick Coleman, University Lecturer in Paediatric Oncology, Cambridge University

Targeting and induction of cell Death in Ewing Sarcoma:

Basic fibroblast growth factor (bFGF) kills Ewing Sarcoma (Figure 1). This is a very exciting observation, because if we can understand how bFGF kills these cells this may lead to new strategies to inhibit the growth of these tumours and treat children with this malignancy.

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HIgh affinity receptors - FGFr, FGFr2, FGFr3 and FGFr4.

bFGF produces it's effects by binding to proteins on the cell surface known as the high affinity FGF receptors (FGFr). There are four high affinity receptors (of which there are many spliced variants) known as FGFr, FGFr2 FGFr3 FGFr4. Previous studies supported by the Adam Dealey Foundation for Ewing Sarcoma have shown Ewing Sarcomas express FGFr1,2,3,4 at the RNA level (Figure 2).

We have also described a novel FGFr3.

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Ewing's cell lines express all high affinity FGFr subtypes.

Variant (Figure 2). This receptor variant is abundantly expressed in a number of different Paediatric and adult tumour types but rarely expressed in normal tissues.

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Tumour specific expression of FGFr3 splice.

We have recently shown Ewing Sarcoma cells express a functional variant FGFr3 protein. Specific expression of the receptor in tumour cells may make this useful for targeting therapy to tumours (Figure 3), potentially improving the efficiency of therapy and reducing some of the side-effects.

When bFGF binds to its receptor the affinity of binding can be modulated heparin sulphate proteoglycans (HSPGs) that are expressed in the surrounding matrix of the tumour cell. In Ewing Sarcoma bFGF appears to bind with HSPGs and its high affinity receptors to produce a stabilised complex that may be essential for induction of cell death by bFGF (Figure 4 & 5).

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Detection of bFGF, FGFr and HSPG protein complex * in ESFT cell lines; stabilised binding that may be important for induction of cell death.

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bFGF stored on.

These studies may lead to the development of novel strategies for improving therapeutic targeting and Ewing Sarcoma cell kill. This work has been carried out by Alison Merrick, Felisa Diaz-Mendez and Dr. Susan Burchill in the Candlelighter's Research Laboratory, ICRF Cancer Medical Research Unit.

Dr Sturle is funded by The Adam Dealey Foundation for Ewing Sarcoma and the Candlelight's Children's Cancer Trust.

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Established since 1995 The Adam Dealey Foundation for Ewing Sarcoma.
The Adam Dealey Foundation is a non-profit charity working in partnership with the Bone Cancer Research Trust to bring public awareness of Ewing Sarcoma and help people who are suffering from.

Site last updated: 22 July 2009

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