Details of Funded Projects
The following projects represent the core of the research sponsored by Cancer Research Wales. To see further details of those projects click on the title.
Professor M Mason – Overview of Research
Zsuzsanna Tabi -Phenotypic characterisation of T cells that infiltrate prostate cancers
Stephen Man - Functional characterisation of T cells that infiltrate prostate cancer
Paul Mitchell -Immune functions of exosomes in cancer
Clinical Trails Unit – Eve Gallop Evans/Jane Darmanin – Various Clinical Trails Projects
Overview of research
The past 2 years has seen a further consolidation of existing research areas, with some very pleasing research output, in the form of publications in high quality peer-reviewed journals. Among them, I would highlight those in Cancer Research, Lancet Oncology, and Journal of the National Cancer Institute. The cancer immunology group are establishing wide-ranging collaborations, both within Cardiff, and elsewhere, and we are finding some unexpected effects of cancer and cancer therapy on the immune system.
Our interest continues into exosomes, very tiny particles produced by both normal cells and cancer cells. Originally, the hope was that exosomes might provide a naturally-made cancer cell product that could be used directly as a cancer vaccine. However, we have shown that, not only is this unlikely to be possible, but exosomes from cancer cells positively switch off the body’s immune system, so the situation is the opposite of what was originally anticipated. Research will now try and unravel the mechanism by which this happens – maybe there will be a way of reversing this effect. Other substances implicated in cancer also impair the immune system – our work continues on the biology of Hepatocyte Growth Factor (HGF) in the spread of cancers, particularly prostate cancer, and there are indications that, as well as promoting cancer spread, HGF may itself impair an immune response. The ways in which cancer evades the immune system are turning out to be many, varied, and complicated.
The Cochrane Unit, involving both research staff and staff in the Cancer Research Wales library, have produced a number of important publications in the last year, working in collaboration with colleagues in England. The aim is to provide the evidence behind the recommendations of the Royal College of Pathologists in defining what characteristics of cancers (of the urological system) will need to be described in reporting for NHS patients in the UK. This is a major contribution to the way in which cancer patients are managed, and has further enhanced the reputation of the Unit worldwide.
A major development in our relationship with Cancer Research Wales has been the grant awarded to the Wales Cancer Bank (WCB). The WCB is a flagship, all-Wales project which is collecting tumour and blood samples from patients in Wales, newly diagnosed with cancer, or with possible cancer. Cancer Research Wales is the only UK Cancer Charity that has directly funded the WCB, as part of their commitment that all research money raised is spent in Wales. We see this as the beginning of a particularly close and fruitful relationship between WCB and CRW, and are proud that CRW uniquely shared our vision for the future of this ground-breaking project. This grant – putting CRW alongside the Wales Assembly Government as our major funder - is allowing us to move beyond the collection and storage of samples, towards processing those samples into a form usable by researchers – for example, by extracting DNA. We will have collected samples from our 2000th patient by early 2008, and to date have received applications for 19 research projects, from the UK and overseas, using our samples. Our hope that the WCB would provide a springboard for international research is coming to reality, and, internationally, WCB is regarded as leading the way in the UK in this field. We are currently collecting samples from seven hospitals in Wales; we need to expand our funding base to enable us to collect samples from all 14 hospitals in Wales, and with the support of our staff, CRW, and above all, our patients, I am confident that we will be able to achieve this.
Malcolm Mason, Cancer Research Wales Professor of Clinical Oncology.
Development and Evaluation of Techniques for the Dosimetric Verification of Intensity Modulated Radiation Therapy
R. S. Cufflin, D. G. Lewis, E. Spezi and A. E. Millin, Medical Physics Department, Velindre Cancer Centre
Radiotherapy involves the use of high energy X-rays for the treatment of cancer. Intensity modulated radiotherapy (IMRT) is a sophisticated form of radiotherapy in which each beam is split into many smaller ‘beam-lets’, resulting in ‘beam modulation’, and is the desirable treatment in situations where the tumour volume is in very close proximity to or impacts on ‘organs at risk’, such as the spinal cord. Verifying the accuracy of treatment delivery is of utmost importance in radiotherapy physics, and the more sophisticated the dose distribution, the more complex the verification solution. This project aims to develop methods for accurate and efficient verification of IMRT.
Over-expression of matriptase-2 suppresses cellular migration and invasion in prostate cancer cell lines
A.J.Sanders, G.Davies, C.Parr, M.D.Mason, W.G.Jiang, Department of Surgery, Wales College of Medicine, Cardiff University, Cardiff
Mortality associated with prostate cancer is due mainly to the spread of tumour cells from the initial tumour to secondary sites such as bone. Proteases play key roles in facilitating the break-away and movement of the tumour cell around the body.
In our current study, we forcibly expressed a newly identified protease, matriptase-2, in prostate cancer cells. The expression of matriptase-2 reduced the aggressive nature of these cells, decreasing their invasive capacity and migratory rates. The results of this study suggest that matriptase-2 may have a suppressive effect on the progression and spread of prostate cancer and may hold potential as a future therapeutic.
Characterising novel variants in candidate genes predisposing to colorectal tumours
CRW funded Ph.D. student – Natalie Jones1
Supervisors – Jeremy Cheadle1 and Julian Sampson1
Other investigators - Duncan Azzopardi1, Anthony R. Dallosso1, Kristilyn
Eliason2, Brant C. Hendrickson3, Edward Rawstorne1, James Colley1, Valentina
Moskvina4, Cynthia Frye2, Richard Wenstrup2 and Thomas Scholl2,3
1Institute of Medical Genetics, Cardiff University, Heath Park, Cardiff,
CF14 4XN, UK.
2Myriad Genetic Laboratories, Inc., 320 Wakara Way, Salt Lake City, UT 84108.
3Genzyme Genetics, 3400 Computer Drive, Westborough, MA 01581.
4Biostatistics and Bioinformatics Unit, Cardiff University, Heath Park, Cardiff,
CF14 4XN, UK
Abstract
We have studied whether rare amino acid changing variants in the adenomatous polyposis coli (APC) gene predispose to colorectal tumours. We analysed 691 unrelated North American patients with colorectal tumours and 969 matched healthy controls. We found that rare amino acid changing variants were more common in patients as compared to controls. Seven out of sixteen variants were shown to be functionally defective in a cell culture system and software-based analyses predicted that over half of the 61 different variants identified were likely to affect function. These data show that multiple rare amino acid changing variants in APC play a significant role in predisposing to colorectal tumours.
Exosomes; A source of Novel Disease Biomarkers in Urological Cancers
Joanne Welton1, Ian Brewis2, Zsuzsanna Tabi 1, John Staffurth 1, Malcolm
Mason 1, Aled Clayton1
1Oncology and Palliative Medicine, 2Medical Biochemistry and Immunology
Exosomes are small round spheres secreted by normal and cancerous cells. We are able to isolate and analyse exosomes from urine, and this may allow us to gain insight into changes occurring within the body during the development of bladder/prostate cancer. Using various laboratory techniques we hope to compare exosomes from the urine of healthy donors and cancer patients . From this we hope to discover new features of bladder/prostate cancer that will form the basis of a novel urine-based diagnostic/monitoring test for cancer.
he Von Hippel-Lindau (VHL)-Ubquitin-PTHrP (YUPrP) Pathway, the Missing Link in Bone Metastasis of Prostate Cancer?
C. Parr. M. D Mason and W. G Jiang
Metastasis and Angiogenesis Research Group, Department of Surgery, Wales
College of Medicine, Cardiff, UK. Department of Medicine, Section of Clinical
Oncology, Velindre Hospital, Cardiff, UK
Parathyroid hormone-related protein (PTHrP) is a molecule that is found at low levels in normal prostate and high levels in prostate cancer. PTHrP is thought to help prostate cancer cells spread to other parts of the body, particularly bone. Presently, it is unclear how these PTHrP levels are regulated. We believe that another molecule, Von-Hippel-Lindau (VHL), may be involved in regulating the amount of PTHrP produced. Therefore, we are investigating a possible regulatory system that may be able to control PTHrP levels. This pathway has been termed the VHL-Ubiquitin-PTHrP pathway and may help us understand how prostate cancer spreads.
DAMIS: Data Analysis in Medical Information Systems Supporting Care Team Decision Making
B. Sissons1, W.A. Gray1, N.J.Fiddian1, A. Bater2, D. Morrey2
1School of Computer Science, Cardiff University, Cardiff, UK
2Clinical Information Unit, Velindre NHS Trust, Cardiff
For the past 10 years cancer care teams of the South East Wales Cancer Network have been collecting data about the patients they have treated. It has always been intended to use this information, in an anonymous form, to support care teams in meeting the needs of new patients. This project seeks the most appropriate way of using this information to accurately answer questions about disease prognosis.
Defining novel targets for immunotherapy of human cancer.
Nunes CT, Mason MD, Man S
Department of Medical Biochemistry and Immunology, School of Medicine, Cardiff
University and Department of Oncology and Palliative Medicine, Velindre
Hospital
The overall aim of this project is to investigate whether a protein called
Bax is a suitable target for immunotherapy. Bax is a protein that controls cell
survival/death. Large amounts of Bax inside a cell push it towards cell death.
However in cancer cells, the amount of Bax is low because Bax is abnormally
digested. This
allows cancer cells to survive. We propose that the digestion of Bax in cancer
cells will produce protein fragments (peptides) that can be recognised by immune
cells (T cells). This project will test whether T cells recognising Bax peptides
can kill cancer cells.
Proteomic analysis of VEGF-induced endothelial cell proliferation and differentiation
Angharad Thomas and Michael Cross
North West Cancer Research Fund Institute, University of Wales, Bangor, LL57
2UW
Cancer progression requires the development of an adequate blood supply which allows the tumour to both grow and then spread throughout the body. Angiogenesis defines the process whereby new capillary blood vessels are formed from pre-existing vessels. Blood vessels are lined by specialist endothelial cells which respond to growth factors, such as vascular endothelial growth factor (VEGF), to stimulate angiogenesis. Our work is concerned with identifying VEGF-stimulated proteins in endothelial cells under conditions of growth (proliferation) and tubule formation (differentiation). We hope that this will identify potential new targets to prevent tumour angiogenesis and ultimately tumour growth.
Developing a method for the analysis of chromatin remodelling to enable excision repair throughout the genome
Yumin Teng, Simon Reed, Raymond Waters
Cancer Studies Interdisciplinary Research Group,
Pathology Department, Medical school, Cardiff University, Tenovus Building
Heath Park, Cardiff CF14 4XN
DNA repair is essential to avoid cancer. 2 metres of packed DNA occur in each of our microscopic cells and it is unclear how repair gains access. This DNA has different factors helping repair gain access to different regions.
We are developing a method to examine how repair is enabled throughout the DNA so we can identify factors enabling repair. This may help develop new cancer therapies; since many anti-cancer drugs damage DNA so we could selectively block repair where the cancer-causing genes reside. If we could determine in individual patients how their DNA repair varies, it may help determine patient outcome.
Isolation and in vitro culture of prostate cancer cells obtained from prostatectomy biopsies
Coleman S, Smith KL, Clayton A, Griffith D, Kynaston H, Staffurth J, Man
S, Tabi Z, Mason MD
Dept. Medical Biochemistry and Immunology, School of Medicine, Cardiff University,
Dept. Pathology & Dept. Urology, UHW, Dept.Oncology & Palliative Medicine,
Velindre Cancer Centre
It is extremely difficult to grow prostate cancer cells in the laboratory. Most prostate cancer cells used for experiments are derived from prostate cancer (PC) that have spread throughout the body. We wish to grow prostate cancer cells, from the original (primary PC) and see the effect of hormones on these cells. By modifying an established stem cell cultures, we have successfully established a method which enables us to grow sufficient numbers of primary prostate cancer cells from small biopsies for experiments in the future.
Phenotypic characterisation of T cells that infiltrate prostate cancers
Tabi Z, Clayton A, Smith KL, Coleman S, Griffith D, Kynaston H, Staffurth
J, Mason MD, Man S.
Dept. Medical Biochemistry and Immunology, School of Medicine, Cardiff University,
Dept. Pathology & Dept. Urology, UHW, Dept.Oncology & Palliative Medicine,
Velindre Cancer Centre
The presence of high numbers of immune cells (lymphocytes) in tumour tissues correlates with longer survival in several types of cancer. We have embarked on a project which will reveal the role of lymphocytes that infiltrate prostate cancer tissues in hormone-treated prostate cancer patients. In the preliminary phase of this project we established methods which enable us to isolate and characterize lymphocytes from prostate cancer biopsies. In these samples we found immune cells that may directly kill tumour cells as well as other immune cells that potentially block this process. The successful establishment of this method enables us to carry out monitoring of immune cells in the cancer tissue of prostate cancer patients.
Functional characterisation of T cells that infiltrate prostate cancers
Smith KL, Coleman S, Griffith D, Kynaston H, Staffurth J, Mason MD, Tabi,
Z, Man S.
Department of Medical Biochemistry and Immunology, School of Medicine, Cardiff
University and Department of Oncology and Palliative Medicine, Velindre Hospital
The overall aim of this project is to study the effect of hormone therapy on (HT) immune cells (T cells), and use this information to develop novel treatments. This year we have developed new methods to isolate and grow T cells from prostate tissue. This has been very successful; we can expand the numbers of T cells from tiny samples up to 4000 fold. These prostate T cells are different from those found in the blood, and can react against proteins found in the prostate. These promising results lay the foundation for future studies on the effects of HT.
Immune functions of exosomes in cancer
J Paul Mitchell1, Lyn Court2, Malcolm D. Mason, Zsuzsanna Tabi, Aled Clayton1
1CRW Research Laboratories, Oncology & Palliative Medicine, School of Medicine,
Velindre Cancer Centre, Whitchurch, Cardiff CF14 2TL
2CRW Research Laboratories , Cancer Services Division, Velindre NHS Trust,
Whitchurch, Cardiff CF14 2TL
Exosomes are complex tiny bubbles of fat, produced in the body in health and disease. We know cancer cells produce exosomes that differ from normal-cell exosomes. The function of cancer exosomes in the body is poorly understood.
White blood cells are important in providing immune protection against cancer. When we treat such cells, taken from a healthy individual, with cancer-exosomes in the test tube, we can see that the cells quickly become defective. They stop dividing in the presence of cancer exosomes, and they no longer kill cancer cells efficiently. Our work shows that exosomes act as a potent mechanism by which cancer cells avoid being attacked by immune system.
Velindre Cancer Centre, clinical trials unit report
Eve Gallop Evans, Jane Darmanin
The Clinical Trials Unit at Velindre Cancer Centre has continued its work in 2006/07 to support patients and facilitate their recruitment into clinical trials. 2006/07 has been the Unit’s most successful year to date, with 661 patients being recruited into clinical trials and 275 patients being offered, but declining or being ineligible for clinical trial entry. This represents an increase of 23% on recruitment figures from 2005.
The Clinical Trials Unit is currently coordinating 163 prospective and ongoing trials, at Velindre Cancer Centre. Also at the outreach hospitals of Llandough, Royal Glamorgan, Princess of Wales and Prince Charles, the CTU is co-ordinating 52 studies. We are therefore able to support and facilitate recruitment into both national and international studies.
Support for local research studies is also an area of increasing activity. Dr J Staffurth, Dr M Adams and Dr Jason Lester are active researchers, and support for local research is a high priority. The contribution received from Cancer Research Wales towards supporting and facilitating such work is gratefully acknowledged and some of the projects include:
- Exploring the introduction of fiducial markers (gold seeds) prior to prostate radiotherapy to aid tumour localization. We plan to use such technology to deliver dose escalated radiotherapy within a shorter overall time.
- Investigating the immunological effect of radiotherapy for localised prostate cancer delivered by either external beam radiation or brachytherapy
- Investigating the immunological effect of systemic therapies for prostate cancer (such as the chemotherapy)
- Investigating the treatment of patients with non small cell lung cancer by treating with individualized, dose adjusted radical radiotherapy.
Verification of Stereotactically Guided Radiotherapy
Tony Millin, Geraint Lewis: Medical Physics Department Velindre Cancer Centre, Whitchurch Cardiff
For the successful treatment of brain tumours it is important to deliver a high dose to the tumour whilst avoiding healthy tissue. An advanced radiotherapy technique employed at Velindre Cancer Centre is that of stereotactic radiotherapy in which a custom made mask is used to immobilise the patient with respect to a frame enabling small fields to be used. However these small fields present significant problems in determining the doses delivered and may become a limiting factor in the treatment offered to the patient. A study involving Monte Carlo techniques in which stereotactic treatments are simulated using advanced computing techniques has been undertaken. This has led to the development of models to validate specific dose systems for treatments used currently. It is hoped that this will be extended to more difficult situations which will add to the understanding of the dosimetry in stereotactically guided radiotherapy.
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