Details of Cancer Research Wales funded projects
Tackling prostate cancer with Cardiff University
A joint study with Cardiff University, funded by the Medical Research Council (MRC) and led jointly by Professor Malcolm Mason, Cancer Research Wales Professor of Clinical Oncology, School of Medicine and Professor David Dearnaley of the Institute of Cancer Research, examined the long-term effect of sodium clodronate on men with advanced and localised prostate cancer Read more of this article.
Cancer Research Wales Open Day
Every January Cancer Research Wales holds an Open Day where you can find out more on all things funding related. Please feel free to download any of the related Open Day handouts below:
ISCO/CANISC booklet
ISCO, Information System for Clinical Organisations allows any number of organisations to record assessments, treatments and follow-up care into a common patient casenote, which any health care professional caring for that patient can access, thus giving a full picture of each individual’s care wherever that person happens to be treated. Download.
Priority report
Multiple Rare Nonsynonymous Variants in the Adenomatous
Polyposis Coli Gene Predispose to Colorectal Adenomas. Download.
Funded research
Cancer Research Wales funded Research in Metastasis and Angiogenesis Research Group. Download.
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.
Dr John Pritchard CBE, Chairman, Cancer Research Wales Scientific Committee
Dr John Pritchard CBE, Chairman, Cancer Research Wales Scientific Committee
The demands for the funding of cancer research in Wales continues to grow as the Charity’s level of income increases, building on the success of 40th Anniversary Year’s activities. As a consequence the work of expert clinicians and scientists from outside Wales, who give freely of their time to peer review new research proposals has increased considerably and is greatly appreciated – without their help we would not be able to maintain the high level of research quality.
All of this places a considerable burden on existing administrative capacity and I am, on behalf of the Scientific Committee, most grateful to all those who help to ensure that the process runs smoothly.
Whilst this still remains vitally important that we continue to increase our support for Studentships for scientists wishing to pursue a career in cancer research leading to a higher degree our research portfolio continues to grow.
The following abstracts give a flavour of the variety of research supported. Additionally, it is important to recognize the success or the Wales Cancer Bank establishing itself as a world leader in tissue banking, where the quality and analysis of stored tumour samples is paramount.
This year has also seen the planning and organization for an inaugural CRW Research Symposium to be held in November 2008. This will be another ‘first’ for the Charity and an opportunity to demonstrate to the research community and health care professionals in Wales the diverse and important contribution that CRW makes to improving the understanding of the cancer process and ultimately better treatment and care for patients diagnosed with cancer.
The Wales Cancer Bank – providing high quality material for cancer research
Gerry Thomas, Director of Scientific Services, Wales Cancer Bank
The Wales Cancer Bank (WCB) is a Welsh Assembly Government and Cancer Research Wales funded initiative that aims to collect blood, serum and tissue from all patients undergoing treatment for cancer in Wales. The WCB was established in 2004 and has since consented over 2500 patients. The current collection includes 17 tissue sites - the largest collections being breast, colorectal, prostate, bladder, renal, head and neck and ovarian. Biological data is linked-anonymised to the all Wales electronic clinical database (CanISC), and consent allows for future access to clinical outcome data. WCB is licensed by the Human Tissue Authority and approved by NRES as a Research Tissue Bank, obviating the need for researchers using material from the bank to apply to NRES for approval of their research projects. Currently, WCB holds donated tissue from 2290 patients and has received 31 applications from researchers in the UK and Europe to access samples. All applications are reviewed by an external, international Scientific Review panel and to date, 16 projects have been supplied with a range of biosamples.
Biological material is subject to pathological and molecular biological QA prior to release in order to validate the SOPs used and to ensure that all samples are fit for purpose. H and E sections are taken from each frozen block and stored digitally. The percentage of tumour epithelium and assessment of lymphoid infiltration and necrosis is made by a pathologist. 70-80% of tissue blocks from breast, colorectal, renal and head and neck cancers but only 10% of prostate blocks contain more than 81% tumour epithelium. RNA and DNA are extracted to a strict protocol using Qiagen technology. Yield and purity (260/280 and 260/230 ratios) assessed using a nanodrop spectrophotometer. RNA integrity is assessed using an Agilent Bioanalyser and samples that gave a RIN of >7 are deemed to be suitable for downstream technologies such as 3’ Affymetrix arrays. 60% of samples from breast and prostate cancer, but only 40% of samples kidney and colon cancers reach this quality standard. DNA extracted from the same tissue samples as the RNA showed pure, high molecular weight (>10kb) DNA suitable for use in array based technologies.
The Wales Cancer Bank has established itself as a world leader in human cancer research tissue banking. In addition to collecting material from NHS Pathology Departments in Wales, it also hosts clinical trials for the WCTN, MRC and CRUK, and provides pathological and molecular biology QA for clinical trials when requested to do so.
Targeting cancer metastasis and angiogenesis
AJ Sanders, L Ye, TA Martin, WG Jiang and MD Mason
(Metastasis and Angiogenesis Research Group, Cardiff University School of Medicine)
The spread of cancer cells can severely influence the quality of life and may lead to the subsequent death of the patient. This spread to a distant secondary site (metastasis) is a complex process in which cancer cells frequently alter the expression of a number of genes to facilitate their travel and survival outside of the primary tumour mass. The metastatic ability of cancer cells can be enhanced by a number of growth factors such as the Hepatocyte Growth Factor (HGF). Current research within the Metastasis and Angiogenesis Research Group (MARG) is assessing the potential of targeting a number of molecules involved in the HGF signalling pathway and whose expression is frequently enhanced during this metastasis process as a method to slow or inhibit the rate of cancer spread.
Further work within the group is also looking into the potential of targeting cancer angiogenesis (the growth of new blood vessels to the tumour). HGF can also regulate the angiogenesis process and research is currently being focused on identifying and targeting molecules which may be vital to this HGF enhanced angiogenesis
Exosomes in Cancer
Aled Clayton, J Paul Mitchell, Joanne Welton, Lyn Court, Zsuzsanna Tabi, John Staffurth†, Malcolm Mason† , Cancer Research Laboratories
Cancer cells can manipulate other non-cancer cells, and this ability is important to the success of cancers in growing and spreading. Our group has been investigating small bubbles of fat, called exosomes, which cancer cells produce; studying how exosomes act as a mechanism for abnormal changes in other cell types during cancer.
Currently there are three themes under investigation by the team. Firstly, it is important to understand what molecules exosomes have as this will have a direct bearing on what exosomes do in the body. Using sophisticated technological tools to identify novel protein molecules in exosomes. The work holds potential to be developed into new tests for cancer.
Secondly we continue to examine the complex effects that cancer exosomes have on the immune system. We have found several ways by which exosomes can essentially switch off immune responses. Cancer exosomes may help the cancer grow, by assisting in immune evasion.
How the immune system works in people with cancer and how we can measure it.
Lisa Spary and Saly Al-Taei, Cancer Research Laboratories
Cells of the immune system can sometimes be observed in human cancers. Research has shown that the presence of these immune cells, such as T cells, can significantly improve the survival rate of patients when compared to those patients without such immune cells in the cancer tissue. This has been shown in several cancers including colon, bladder, ovarian and prostate cancer. The immune cells also produce molecules, such as gamma-interferon, that can be used to predict the progression of the disease more successfully than looking at the expression of genes generally associated with the cancer. Still, we know relatively little about the exact role the immune system plays in protecting us from the development of cancer and how it may become an effective treatment for cancer.
Ongoing experiments in our group are trying to reveal how the immune system works in cancer patients. We study both the positive aspects, such as the activity of T cells against cancer cells in the patients, and also the negative ones: how cancer cells escape the attack of T cells. We are especially interested to see how conventional treatments, such as hormone or radiotherapy in prostate cancer, affect the immune system. What we learn from these experiments will enable us to decide what immune intervention and in what time relating to the conventional treatment would improve best the patients’ chances of recovery or longer survival and better quality of life.
The fellowship of the Ring
Simon Janes and Thomas Caspari, School of Biological Sciences, Bangor University, Bangor, North Wales
When JRR Tolkien wrote “One Ring to rule them all, One Ring to find them, One Ring to bring them all”, he surely did not think about the ring-shaped Rad9-Rad1-Hus1 protein complex. But without knowing it, Tolkien described exactly the biological role of this protein complex that may contribute to the development of breast, prostate and ovarian cancer.
Intriguingly, every second breast tumour contains elevated protein levels of Rad9, but not of the other two subunits of the ring. This strongly indicates that Rad9 promotes uncontrolled cell growth independently of the ring. This Cancer Research Wales funded PhD project aims to unravel these novel tumour-promoting functions of Rad9.
To generate a Rad9 protein that is unable to form the ring, we constructed cells that express a truncated Rad9 protein that misses the first 49 amino acids. While these cells are sensitive to many different DNA damaging agents, they are resistant to the anti-cancer drug camptothecin. This observation may have important implications for the treatment of patients, because many breast tumours become resistant to this drug. A major aim of our work is therefore to identify the signalling pathways which are engaged by the truncated Rad9 protein giving rise to the drug resistance.
Data Analysis in Cancer Information Systems
Alysia Skilton1, Dave Morrey2, W. Alex Gray1, Omnia Allam1, Hazel Bailey2
1 Cardiff University, School of Computer Science
2 Velindre NHS Trust, Clinical Information Unit
With the growing emphasis on collaboration in healthcare, there is significant demand for information systems that can streamline communication, particularly across organisational boundaries. Programmes such as the Welsh Clinical Portal and Connecting for Health are addressing the challenges of bringing together information that is currently distributed across multiple locations and systems. While this is a critical step forward, there is still a need for systems that will more actively support collaboration between practitioners working in different locations. This work aims to investigate how information sharing systems can be extended to address issues of providing targeted information as well as actively supporting communication and collaboration.
It is proposed that treating the multidisciplinary group of people who have interest in a particular patient as a team, and storing administrative information about this team will allow for more efficient and targeted communication. For each patient, the system will keep track of team members and the role that they play in the patient’s care team. This will allow the system to identify who is most likely to be interested in a particular change to the patient’s condition and what information will most likely be required. In this way, it will be possible to ensure that those who are most interested are kept informed with the right information while reducing information overload for those who are not.
Additionally, the system will incorporate the use of policies to facilitate standard communications. When a new care episode is entered into the system, details of the episode will be checked against the policies. If policy indicates that it is necessary for other team members to be notified, the system will use the team information to identify to which practitioners this applies, and an appropriate notification will be provided through the system to the appropriate people. This will again reduce information overload and provide additional protections for patient data while simultaneously ensuring that practitioners are kept informed of important changes to their patients’ health in an efficient way.
Healthcare information systems that provide comprehensive patient information access will be a major step forward. However, challenges to communication and collaboration will still exist for healthcare teams. This work explores these challenges and investigates how new technologies can be leveraged to address issues of both targeted information sharing as well as communication and collaboration that goes beyond pure information exchange.
Velindre Cancer Centre Clinical Trials Unit
E Gallop-Evans, Director Velindre Cancer Centre Clinical Trials Unit
Cancer registrations in Wales continue to rise each year, and despite improvements in early detection and treatment, only modest gains in cancer mortality have been achieved over the past decade. Successful development of new cancer treatments requires translation of laboratory research findings into clinical practice, with clinical trials providing robust evidence for these new treatments.
Velindre Cancer Centre Clinical Trials Unit was established by Professor Tim Maughan in 1994, with the recognition that clinical research can lead to improvements in the quality of patient care. The Unit now has a staff of 22, and is currently coordinating 196 prospective and ongoing trials. 2007/2008 has been the Unit’s most successful year to date, with 848 patients being recruited to clinical trials. With a cancer incidence in SE Wales of 6900, this represents a recruitment rate of 12.3%.
In the 40th anniversary year of Cancer Research Wales, there is much to celebrate. CRW has played a crucial role in supporting research in local institutions in Wales. We are particularly keen to support local researchers with international reputations, including Professor Malcolm Mason and Dr Malcolm Adams.
This would not be possible without generous support from CRW. We look forward to continuing to work with CRW so that we can offer cancer patients in Wales high quality clinical trials, and thus improve care for all patients.
Dosimetric Verification of IMRT
R. S. Cufflin, E. Spezi, D. G. Lewis and A.E. Millin, Medical Physics Department, Velindre Hospital
Intensity Modulated Radiation Therapy (IMRT) is a sophisticated form of X-radiation therapy for cancer, involving dynamically moving shaped beams, which conform to the tumour volume. Extensive verification procedures are required to ensure treatments are delivered accurately, to comprehensively sample the complex dose distributions involved, impacting on the tumour volume and radiation-sensitive ‘organs at risk’. An IMRT underdose may result in reduced tumour control whilst an overdose may result in radiation induced injury.
Conventional dosimetry methods use ionisation chambers, thermoluminescent dosimeters (TLDs) or diodes, but these are only able to provide point-by-point sampling. Film dosimetry is able to provide 2-dimensional information of high resolution but film processors are becoming obsolete as many radiotherapy centres are now turning to digital picture archiving and communications (PAC) systems. Electronic portal imaging devices (EPIDs), comprised of an array of photodiodes, are an alternative. They are primarily used to verify the patient position during treatment by imaging the X-radiation beam exiting the patient, but they also have the potential to be used as efficient dose verification tools of high spatial resolution.
Our current approach combines Monte Carlo (MC) dose calculations with the information provided by EPIDs. MC simulations involve computationally tracking the paths of particles, interaction-by-interaction using probabilistic methods and the technique is now widely accepted to calculate the most accurate dose distributions in the presence of patient contour and anatomical inhomogeneities. MC models of the treatment machine in combination with the EPID enable the dose to the detector to be accurately predicted and compared directly with acquired images. The aim is to use our technique to verify all patient IMRT plans before treatment commences before moving onto dose verification during treatment.
Investigating the relationship between tumour-based molecular markers, germline missense variants and response to chemotherapy for advanced colorectal cancer
Chris Smith1, S. Idziaszczyk1, R. Harris1, M. James2, B. Jasani2, R. Adams3, T. Maughan3, COIN
Trial Management Group and J. Cheadle1.
Institute of Medical Genetics, Department of Pathology, Cardiff University and Velindre Hospital
Oncology Department
Intensity Modulated Radiation Therapy (IMRT) is a sophisticated form of X-radiation therapy for cancer, involving dynamically moving shaped beams, which conform to the tumour volume. Extensive verification procedures are required to ensure treatments are delivered accurately, to comprehensively sample the complex dose distributions involved, impacting on the tumour volume and radiation-sensitive ‘organs at risk’. An IMRT underdose may result in reduced tumour control whilst an overdose may result in radiation induced injury.
Conventional dosimetry methods use ionisation chambers, thermoluminescent dosimeters (TLDs) or diodes, but these are only able to provide point-by-point sampling. Film dosimetry is able to provide 2-dimensional information of high resolution but film processors are becoming obsolete as many radiotherapy centres are now turning to digital picture archiving and communications (PAC) systems. Electronic portal imaging devices (EPIDs), comprised of an array of photodiodes, are an alternative. They are primarily used to verify the patient position during treatment by imaging the X-radiation beam exiting the patient, but they also have the potential to be used as efficient dose verification tools of high spatial resolution.
Our current approach combines Monte Carlo (MC) dose calculations with the information provided by EPIDs. MC simulations involve computationally tracking the paths of particles, interaction-by-interaction using probabilistic methods and the technique is now widely accepted to calculate the most accurate dose distributions in the presence of patient contour and anatomical inhomogeneities. MC models of the treatment machine in combination with the EPID enable the dose to the detector to be accurately predicted and compared directly with acquired images. The aim is to use our technique to verify all patient IMRT plans before treatment commences before moving onto dose verification during treatment.
Verification of Stereotactically Guided Radiotherapy
Tony Millin, Geraint Lewis.
Medical Physics Department,Velindre Hospital
Stereotactically guided radiotherapy is used to remove the uncertainties associated with medical imaging and patient positioning to reduce the size of safety margins applied to radiotherapy treatment volumes enabling higher doses to be delivered to the tumour whilst sparing healthy tissue. Consequently radiotherapy field sizes used in this technique are much smaller than those used in conventional radiotherapy and often so small that the uncertainties associated with their measurement present a challenge for radiotherapy physicists in performing an independent measurement or calculation of the dose predicted by the treatment planning system. Methods based on conventional techniques have been used to make definitive calibrations of radiotherapy equipment used in this situation but are difficult to use routinely to determine 3-dimensional dose distributions and contribute to the routine verification of patients treated with this advanced technique.
In order to solve this problem of producing an accurate 3-D dose distribution useful for routine patient by patient verification of stereotactic radiotherapy a Monte Carlo model has been developed of the treatment machine eliminating uncertainties due to perturbations caused by the presence of conventional measurement devices. The Monte Carlo model which builds up a picture of the dose distribution by modelling individual particles passing through the patient allows full 3D dose distributions to be calculated using patient specific geometry and therefore allows independent verification of stereotactic treatments in all including the most complex of situations.
After a brief introduction to Monte Carlo Methods and Stereotactic radiotherapy results of the validation of the model are presented showing good agreement between simulated and measurement where experimental uncertainty is low together with clinical examples of the model used to validate the dose distributions calculated by the routine treatment planning system.
Cancer Research Wales
Professor M D Mason
Professor of Clinical Oncology and Honorary Scientific & Medical Adviser to CRW
The Wales Cancer Bank has continued to flourish over the last year, and we are proud to be regarded as CRW’s major flagship project, co-funded with the Wales Assembly Government. Over the last year in particular, the number of research projects which have been supplied with human cancer samples has grown, and the system for rapid scientific evaluation and approval appears to be working well. We now have a presence in seven hospitals in Wales, and plan to expand into one further site in the next year. We could not have achieved this without the support of Cancer Research Wales, and we thank all those who have donated money; we could not do this without you. On the National level, WCB has the distinction of hosting more sample collections for UK multicentre clinical trials than any other organisation, and it is gratifying to see our expertise in this field becoming recognised.
The last year has seen further consolidation of our research programme in cancer immunology, with several publications in high quality journals, and presentations at National and International meetings, including that of the American Society for Clinical Oncology. It is becoming clear that our co-location with patients undergoing chemotherapy and radiotherapy is a real advantage, and greatly facilitates the collection of fresh blood samples for analysis, something which we believe is of major importance as we are committed to generating data from real patients, as opposed to artificial laboratory models. The feedback from our visitors at the laboratory open days has reinforced that view; our patients and supporters of the Charity have a particular interest - rightly in my opinion - in understanding what happens in the real-life situations that we face daily in the clinic.
The Cochrane Unit has continued to develop and publish systematic reviews, and we are particularly proud to have been able to support a number of young researchers, clinical and non-clinical, whose interest in this important area has, we hope, been cemented by their experience of working with us.
The present financial climate is a difficult one for all of us, but is particularly difficult for research. There is always the danger that, at a time of financial difficulty, the ability of a Charity to fund all of the high quality research projects that it wants to becomes stretched, and I want to thank all those who support CRW for doing so. CRW is the second-largest funder of cancer research in Wales - they play a vital role in our Nation’s research, and the drive to beat cancer - for the one in three of us who will develop cancer in our lifetimes, CRW could make all the difference. We are certainly working on it.
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
1 - Institute of Medical Genetics, Cardiff University, Heath Park, Cardiff, CF14 4XN, UK.
2 - Myriad Genetic Laboratories, Inc., 320 Wakara Way, Salt Lake City, UT 84108.
3 - Genzyme Genetics, 3400 Computer Drive, Westborough, MA 01581.
4 - Biostatistics 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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