YCR research 2004/5

University of Bradford
The Institute of Cancer Therapeutics

The Institute of Cancer Therapeutics is about discovery and evaluation of new treatments for cancer. The primary objective of the Institute is to take a new cancer medicine from concept through to the clinic. This combination of skills within one centre at Bradford is probably unique within the universities of the region. Professor Laurence Patterson CChem FRSC joined the new Institute as Director in January 2005.

The Institute is part of the School of Life Sciences at the University of Bradford and incorporates the Tom Connors Cancer Research Centre. There has been a strong presence and history of excellence in cancer research at Bradford for over 30 years.

Historically the Institute progressed molecules to the clinic developed by other institutes and companies. In this way studies performed previously within the Institute contributed significantly to the understanding of factors which influence the response of tumours to cytotoxic therapy. This approach has enabled the development of a number of novel anticancer therapies.

Now, funding from Yorkshire Cancer Research enables the new Institute of Cancer Therapeutics to establish expertise in Medicinal Chemistry at the University of Bradford. This new team of chemists, under the direction of Professor Patterson, seeks to specifically identify and create novel small molecules for cancer therapy. This works in concert with the considerable experience of the Institutes team of cancer researchers to investigate the interactions of the new molecules with targets that can be harnessed to specifically kill cancer cells.

The Yorkshire Cancer Research funding has enabled the appointment to the Institute of Cancer Therapeutics of a Senior Lecturer in Medicinal Chemistry and two Lecturers in Medicinal Chemistry. The expertise of the new YCR funded Chemistry programme will develop agents that have revealed activity in tumours which have developed resistance to standard chemotherapy. These agents offer the potential to override a major cause of failure of therapy whereby the cancer cells possess or develop ways to prevent conventional cancer therapy destroying them.

The expertise of the new YCR funded team at the Institute will also enable the development of new anticancer agents which use the properties of the cancer cell to release the active agent specifically at the cancer cell. This strategy protects normal cells from the toxic effects of the anticancer agent. Specific research that the Yorkshire Cancer Research funded team is concerned with is agents that are specifically activated in low oxygen regions of solid tumours. Other strategies involve enzymes that are highly expressed in cancer cells that can locally activate new agents specifically in the tumour.

The Medicinal Chemists at the Institute are additionally looking to develop anticancer agents which prevent tumours spreading to distant sites. This metastatic process is a major cause of failure of therapy where cells gain entry to the blood stream and migrate to create tumours throughout the body.

In developing expertise within the Institute of Cancer Therapeutics, Yorkshire Cancer Research funding is allowing the creation of a new proteomic facility. Proteomics involves the identification and measurement of many proteins simultaneously using specialist analytical (mass spectrometry) equipment. A new senior lectureship post and mass spectrometry equipment funded through a grant from Yorkshire Cancer Research will be used to measure globally proteins extracted from tumour specimens. By comparing the levels of different proteins in cancer cells and normal cells it is possible to then understand more about the cancer process and develop new anticancer agents that are targeted at the protein contained in tumour cells and not in normal tissue. This in turn helps to prevent associated side effects with cancer chemotherapy.

Exciting times are ahead for the Institute of Cancer Therapeutics with the new Yorkshire Cancer Research funded medicinal chemistry team. The new 6.5million facility due for completion May 2006 will include a whole floor of medicinal chemistry facilities dedicated to new agent synthesis. This new facility will be located on the main campus and will be linked via the new Norcroft Conference Centre to the Institute of Pharmaceutical Innovations expertise in drug formulation and the University of Bradfords analytical centre. This facility houses both the high field NMR and high resolution mass spectrometry facility used by the Yorkshire Cancer Research team of chemists. The purpose-built new Institute of Cancer Therapeutics is being funded by the University of Bradford including support obtained from the Science Research Infrastructure Fund, as well as European Regional Development Funding. The new institute will include a cancer bioscience incubator facility which will assist attraction of the significant funds needed to turn the Yorkshire Cancer Research new anticancer agents into cancer medicines.

University of Hull
Centre for Magnetic Resonance Investigations

Achievements during 2004-5: The first GE LX whole body 3 Tesla MR system in the UK was installed at the CMRI in Hull in May 2004. This system is twice the field strength of currently used machines and provides twice the signal, resulting in better image quality. The system is capable of all types of advanced imaging as well as multi-nuclear spectroscopy, which provides chemical information about tissues. This translates into improved cancer diagnosis and staging and optimised treatment for patients.

The research programmes include breast, prostate, gynaecological cancers, the role of MR in radiotherapy delivery, and optimising delivery of MR information to surgeons. There is a move to replace systemic cytotoxic chemotherapy with novel targeted agents, which act by inhibiting specific requirements or functions of tumour cells.

Breast Programme: The breast research programme currently investigates the local staging of tumour and the prediction and monitoring of response of locally advanced cancer to chemotherapy or hormonal manipulation using MR spectroscopy, diffusion weighted (random movement of water molecules which is altered in disease states) and R2* imaging (reflecting tissue oxygenation status) and textural analysis of tissues. The work is carried out on one of only three prototype breast receiver coils available globally.

The primary aim of breast MR spectroscopy is the quantification of tissue choline, which can be significantly elevated with malignancy. This is being used together with imaging to assess response to treatment. Preliminary work indicates that baseline pharmacokinetic data, and possibly both R2* and diffusion-weighted imaging can predict response of locally advanced breast cancer to neoadjuvant chemotherapy, allowing early alteration in clinical management.

Several reports indicate improved clinical management of patients scheduled for wide local resection of tumour following the addition of MR imaging to current pre-operative assessment. A multi-centre randomised controlled study of 1,800 patients (COMICE), developed and co-ordinated in Hull, is currently in progress.

Gynaecology Programme: This is a relatively new programme for the unit and an area of MR imaging that has been poorly researched, offering niche opportunities. It is now well recognised that neither CT nor USS are as accurate as MRI in the evaluation of pelvic pathology and in this centre MR is used for: the differentiation of benign from malignant pelvic masses; staging tumours essential for optimisation of initial management; assessment of response to treatment in both the neoadjuvant and adjuvant settings; and the detection of tumour recurrence if tumour markers rise.

Patients with tumours of the cervix uteri and endometrium are also being assessed to determine the extent of infiltration of the overlying tissues. Imaging of the vagina and vulva to assess the extent of malignancy is also being developed. Our overall diagnostic accuracy of MR imaging of gynaecological malignancies is 93%.

For advanced cancer, the role of 3T imaging to assess response to chemotherapy is being investigated. For advanced tumours of the cervix uteri that are commonly treated by chemoradiotherapy, we will shortly be examining the role of MR imaging and spectroscopy in predicting response to treatment and the possibility of using MR data to delineate the radiotherapy treatment field and minimise side-effects on surrounding tissues.

Prostate Programme: MR imaging is continuously being developed to improve techniques that increase the accuracy of differentiating benign from malignant tissues. Over the last few years we have developed different sequences to aid diagnostic accuracy. As a consequence staging accuracy is improved with specificity values ranging from 80-85%, but differentiation of tissue types may still be problematic. As a consequence we are now examining the addition of MR proton spectroscopy in pre-treatment assessment.

Prostatic malignancy is frequently multi-focal, and as a consequence whole-gland treatment must be undertaken. Foci of tumour that demonstrate more aggressive changes may benefit from a boost radiotherapy dose and MR data is being used to plan radiotherapy delivery and simulate the effects of targeted therapy. Consideration is being given to movement of the prostate within the pelvis, which affects the planning process. This work will benefit from planned collaboration with GE Munich who will provide a prototype endorectal coil for improved signal reception.

Work has already been reported on the role of diffusion-weighted and diffusion tensor imaging in differentiating between tissue types in the prostate. The repeatability and reproducibility of this technique has been examined to allow its use in monitoring response to treatments, such as radiotherapy and interstitial photodynamic therapy, when residual tumour can be difficult to distinguish from scarring.

Other studies: These have revolved around the use of MR imaging and spectroscopy in head and neck, and brain tumours. Radiotherapy planning of head and neck cancer relies on accurate delineation of tumour extent and its relationship to normal structures. The current YCR funded study, carried out with the University of Sheffield, incorporates information from different sequences in the planning process and uses simulation techniques to compare the relative doses of radiotherapy administered to critical organs based on plans developed with CT information alone and combined with MR data. 3D verification of the proposed plan is under investigation using BANG gels, which polymerise on exposure to radiotherapy and change MR signal characteristics.

Information from imaging, spectroscopy and functional MR imaging of the brain is being combined to better delineate the clinical tumour volume. This work aims to identify areas in which greater tumour cell kill rates could be achieved, if a boost dose was applied. Such techniques require careful quality assurance, advanced software programming and comparison with conventionally employed methodology.

University of Leeds

There has been a long history of cancer research in the University of Leeds and the associated teaching hospitals, dating back to the founding of YCR. The current state of cancer research in Leeds is very buoyant with a substantial number of projects funded by YCR both in the University and in St Jamess University Hospital. YCR-funded projects are principally located in the Faculty of Biological Sciences (situated on the main campus of the University) and the School of Medicine (based both on the main campus and at St Jamess).

Projects in Biological Sciences tend to be of a more fundamental nature, involving research on viruses and cancer, analysis of gene expression in cancer cells and the role of protein degrading enzymes in prostate cancer.

In the School of Medicine at St Jamess, there are both fundamental and clinical projects in cancer research, concerning molecular aspects of haematological cancers, immunotherapy of cancer, DNA damage in bladder cancer cells, the role of bacterial infection (Helicobacter pylori) in gastric cancer and the mechanisms involved in oral cancers.

On the University campus, The School of Medicine hosts projects on colon cancer and the molecular epidemiology of oesophageal and skin cancer.

The University continues to make improvements to infrastructure for research and this has direct beneficial effects on cancer research at Leeds. The Faculty of Biological Sciences is undergoing major organisational changes to increased research activity and cancer research will continue to be a major focus of its activities. The research laboratory facilities are also being radically improved using national funding schemes.

The Leeds Institute for Genetics, Health and Therapeutics (LIGHT) was formally opened in 2005 in a new purpose-built building on the University campus. This houses researchers from Medicine and Biological Sciences, including those engaged in YCR projects on cancer molecular epidemiology.

A new Institute of Molecular Medicine, Epidemiology and Cancer Research (IMMECR) will open 2005/2006 in a purpose-built building on the St Jamess campus, funded in part by YCR. This will bring together cancer researchers in the School of Medicine currently based on both campuses and there will be close links with NHS facilities including a new Oncology Centre, providing excellent resources for cancer research going from laboratory to patient.

The Universities of Leeds and Bradford have joined together to form a major site of the National Cancer Research Institute and the National Cancer Research Network, which are national schemes designed to improve the numbers of patients entering clinical trials for cancer and to speed developments in laboratory-based research into the clinic. There are also excellent interactions between YCR-funded researchers and those supported by other cancer charities in Leeds, such as Cancer Research UK and Candlelighters.

Looking to the future, YCRs role in cancer research in Leeds will continue to be of great importance. The increasing integration of cancer research in Leeds and the provision of state-of-the-art buildings and facilities are expected to have a major impact on the development of new concepts and therapies for cancer in the 21st century.

The Yorkshire Cancer Research Photodynamic Therapy Group

It is not often that a completely new approach to treating cancer becomes a real possibility, but this was exactly the situation in the mid-1980s when photodynamic therapy (PDT) emerged. This is a treatment which involves the combined action of a photosensitising drug (often called a photosensitiser) and light to give a beneficial effect. With either the drug alone, or the light alone, there is no effect.

The Leeds PDT Group began with the kind of coincidences which seem to characterise so many new developments. Professor Stan Brown had been invited to speak at a conference in the USA, on this newly developing field. His lecture was on research about porphyrins, a group of naturally occurring compounds derived from haemoglobin. These compounds also happened to be of interest as drugs for the newly developing approach of PDT. There he met Roy Parker, who was Professor of Medical Physics in Leeds and who was also interested in PDT, but from the point of view of the light, rather than the drug. Professor Parker had already had some discussions with others in Leeds, including Dr (now Professor) John Griffiths from the Department of Colour Chemistry who was interested in PDT from the chemistry standpoint and with Dr Dan Ash, a Clinical Oncologist from Cookridge Hospital, who wanted to use PDT to treat patients. Discussions had already been held with Douglas Shortridge (then Chairman) and officers of YCR, and soon all parties came together and the Leeds PDT Group was born.

Tragically, Professor Parker died very soon afterwards and the leadership of the group was taken over by Professor Brown. Since that time, YCR has invested strongly in the Group, with successive grants and support for individuals. Through this outstanding level of support the Leeds Group has developed to become one of the world leaders in PDT.

Almost without exception, it is many years before new approaches to cancer treatment become available for widespread use in patients. This is partly because of the time taken to find the conditions where it acts best for patient benefit, and partly because of the strict regulatory hurdles which any new drug treatment has to overcome. PDT has been no exception and it is only recently that we are seeing the technique moving into mainstream medicine, especially in skin cancer treatment. As often happens, there are spin-offs into other areas of medicine and PDT using the drug Visudyne is now the main treatment for macular degeneration (the most common cause of blindness in the elderly), with over one million patients having been treated worldwide.

With the support of YCR, the Leeds Centre has played a major role in PDT development. Treatments have been developed in a number of areas including the lung, oesophagus, skin and brain.

The group carried out pharmacological studies which were used in the approval of the first PDT drug, Photofrin, in 1993 and most other PDT drugs have been tested in the Leeds Centre. One of the Groups main contributions was to develop a special branch of PDT using aminolaevulinic acid. Here, instead of giving a patient a photosensitising drug, a small, naturally occurring molecule is given which the body then itself converts into a powerful photosensitising drug. Although originally invented in Canada, it was first developed in Europe through the Leeds Centre. It is now used widely for the treatment of the most common form of skin cancer. A cream containing the drug is spread over the cancerous area on the skin. After 2-4 hours red light is directed over it for about 15 minutes. After this simple procedure, most of the treated cancers are cured.

Photodynamic therapy is now beginning to make an impact in the management of several other cancers. Exciting data have emerged from the treatment of gastrointestinal cancers with good results in pancreatic cancer and cancer of the biliary system. The treatment of Barretts oesophagus, a pre-cancerous condition, has recently been approved using PDT. In Leeds, working with the YCR Group, Mr Paul Marks has been achieving excellent results with PDT of pituitary tumours. A new approach is being developed for treatment of prostate cancer and new diagnostic techniques using PDT drugs have now been approved for bladder cancer.

The Leeds PDT Group continues to make a leading contribution in many of these areas, especially in the development of new PDT drugs. During the past year, two of the new drugs discovered in Leeds have been undergoing pre-clinical testing to prepare for their first trials in patients. One of these drugs is already in initial clinical trials, though this is currently for anti-bacterial treatment rather than for cancer. Initial results suggest that PDT using this drug is able to greatly reduce infection, for example in chronic ulcers or in MRSA infections. It is planned that the second drug will enter patient trials early in 2006, probably for advanced oesophageal cancer. These trials are being taken forward by Photopharmica Ltd, a company which was established with the support of the University of Leeds and YCR to facilitate the further development of the work of the Leeds PDT Group. Drug development is expensive and needs to be managed by the pharmaceutical industry, allowing YCR and the Universities to focus on the early discovery of new treatments.

The support given by YCR to the development of PDT at Leeds has had major benefits for the region and beyond. More than one thousand patients have been treated with PDT in Yorkshire. Several international conferences have been held in Leeds and Centre staff have made many contributions.

Many medical consultants and scientific staff have been trained in the Group and are now in senior posts in the Yorkshire region, drawing on the research skills acquired and applying these for the benefit of patients. Dozens of research students and postdoctoral staff, initially trained within the group, are now applying their skills throughout the UK and as far away as Australia, Canada, the United States, China and Malaysia as well as many other parts of Europe.

The support given by YCR over a long period has been vital in all of these developments. Without that support, none of these achievements would have been possible.

University of Sheffield
The Institute for Cancer Studies and the Development of Clinical Oncology

This past year has seen the culmination of certain studies funded recently by Yorkshire Cancer Research, together with consolidation of work initiated by YCR programme grants and the start of some exciting new studies. Special highlights on the scientific front include the recent paper in Nature from Dr Thomas Helledays group in the Institute for Cancer Studies describing a novel therapy for the treatment of breast cancer in individuals carrying the BRCA1 or 2 gene mutation. Dr Helleday has found that tumour cells from individuals carrying this predisposing gene mutation are exquisitely sensitive to inhibitors of a protein called poly(ADP-ribose) polymerase (known as PARP). Normal cells in these individuals are not sensitive to the inhibitors, thus the drugs can be specifically directed against the tumours. This can potentially reduce the toxic side effects usually associated with chemotherapy. Since work with various model systems suggests that these inhibitors are non-toxic, these agents may also be suitable for use as chemopreventive agents that could stop tumours from ever occurring in individuals inheriting the BRCA1 or 2 mutations. This would present a major improvement in the quality of life for individuals carrying these predisposition genes. Phase I clinical trials aimed at testing the effectiveness of this promising new therapeutic approach are soon to commence. This work is part of the major research effort in the Institute of Cancer Studies aimed at formulating new therapies for the treatment of cancer based on the genetic make-up of the tumours and the patient.

On the clinical side Sheffield is at the top of the league table for many clinical trials, particularly in breast cancer and lymphoma. Major clinical initiatives include strengthening of bone oncology research (to look at and treat cancer that has spread to the bones) and expansion of research examining the late effects of cancer treatment (particularly second cancers and endocrine (hormonal) malfunction). One highlight has been the award of a prestigious ASCO (American Society for Clinical Oncology) Merit Award (for the third consecutive year) to Dr Janet Brown for her work in cancer-induced bone disease.

All this would not have been possible were it not for consistent and strong support from YCR over many years, which has empowered Sheffield to set up well established programmes in both scientific and clinical research. The main scientific research programme has been based in the YCR Institute for Cancer Studies in the Medical School. This Institute for Cancer Studies was established in 1993 and has major core funding from YCR. In addition programme and project grants have supported research and enabled senior academic staff to win major funding from other prestigious grant giving bodies (for example the Biotechnology and Biological Sciences Research Council, the United States Department of Defense Prostate Cancer Research Initiative and the Breast Cancer Campaign). The Academic Unit of Clinical Oncology was financially endowed by YCR in 1988. Clinical trials research is mainly carried out in the Cancer Research Centre, a purpose-built clinical trials facility at the Weston Park Hospital.

A YCR programme grant enabled core funding for establishing a multidisciplinary clinical team, the model of which was so successful as to attract further major funding from the University of Sheffield, Weston Park Hospital Cancer Appeal, pharmaceutical industry (particularly AstraZeneca) and Department of Health (North Trent was a first wave recipient of National Cancer Research Network monies). There is now an experienced and flourishing Clinical Trials Team conducting meticulous research studies; already over 5,000 patients have consented to being involved in a variety of important clinical trials.

While the scientific and clinical research components are physically separate, excellent interactions exist particularly in the fields of cancer genetics, genetic epidemiology and novel therapies. Other important YCR funded research teams flourish within the Medical School and across the wider University.

Looking to the future, our main strategy is to build on the collaborative and translational research being undertaken in the Institute of Cancer Studies. For example work on colon cancers has shown that a mutant gene (MRE11) increases the sensitivity to one of the chemotherapy agents (camptothecin) used in treating these tumours. Such findings may help identify other tumours that respond favourably to similar chemotherapeutic agents and enable development of new gene-directed therapies.

Extending the research on genetic re-arrangements causing disruption of tumour suppressor genes could lead to a better understanding of the development of cancer; the afore described work on PARP inhibitors is just one aspect of this approach, which is to be put into clinical trial.

Another novel research strategy being explored at the Institute is to attack the causative viral agents responsible for certain cancers, such as cervix carcinoma; study of viral proteins controlling viral DNA replication should lead to the development of specific vaccines or targeted anti-viral drug therapy.

These are just a few of the research projects being undertaken at the Institute of Cancer Studies all of which are very much a testimony to YCRs successful funding support for this major Sheffield initiative. We look back with pride at our fruitful association with Yorkshire Cancer Research and look forward with excitement to continuing strong links, to the ultimate benefit of cancer sufferers everywhere.

University of York

The YCR Cancer Research Unit

The major aims of the research in the CRU are to further understanding, at the molecular level, of human prostate cancer, and to understand the operation of the E2 protein of human papillomavirus and how it affects virus growth and the induction of cervical cancer.

After 20 years of working with human papillomaviruses, we have made the difficult decision to wind down HPV research. This was a reflection on the exciting progress being made on vaccination against cervical cancer, which could lead to the eradication of this common cancer in females, but also reflects the rapid progress that prostate research has made since its inception in York since 1991.

Prostate Cancer Research - The Past: We have made major progress in understanding the genetic changes which underlie the tumour and in finding new and better ways to model the disease in the laboratory. The latter work makes use of our close and long-term collaboration with Mr Mike Stower, Consultant Urological surgeon in York. These cell models are now being used in many laboratories around the world.

The Present: Advanced prostate cancers are remarkably resistant to all forms of chemotherapy and many patients ultimately develop recurrences after both radiotherapy and androgen therapy. This is probably due to the existence of cancer stem cells, which are like a root from which the bulk of the cancer can grow. The work of Dr Anne Collins in identifying the nature of these cells, which constitute less than 0.1% of any tumour, has produced an almost unique source of raw biological materials which allow us to understand the novel biology of these cells.

Cancer stem cell cultures are considerably more invasive than some of the most invasive cancer cell lines and 20 times more invasive than stem cells from non-malignant tissues.

We now have ideal material to study the genetics of the tumour, and the critical cell signalling pathways, which tell the prostate cancer stem cells to survive above all others.

For several years the CRU has been instrumental in exploring gene therapy as a viable treatment option for prostate cancer. A research programme with five partners from around Europe has just finished, and in January we received confirmation of approval for a bigger (and hopefully even better) programme of research, called GIANT, which involves 14 laboratories around Europe with total funding of 9.7 million euros. The entire programme is co-ordinated from the CRU in York.

In York, our gene therapy studies use a virus from insects (baculovirus), which we have humanised to enable it to attach to and infect prostate cancer cells, resulting in a stable medicine, which is capable of injection into prostate cancer patients.

YCR and the University are major share-holders in a spin out company (Pro-cure Therapeutics). The company has been instrumental in patenting our basic science, to protect it from unauthorised exploitation. This allows us to talk to major pharmaceutical companies and other organisations, who have the finance available to turn the basic research funded by YCR into clinical treatment for patients with prostate cancers.

The Future: Prostate cancer research is now one of the most vibrant and fast moving. For us, the advent of stem cell isolation techniques looks set to revolutionise our ability to model the disease, and the prospects of a cure, or at least a longer lasting treatment for prostate cancer, should improve dramatically.

Gene therapy remains a viable treatment option, particularly when the tumour develops resistance to the standard therapies, but we must ensure that such an expensive new treatment is both specific for the cancer cells, and has minimal side effects.

Human Papillomavirus Research: There can now be little doubt that human papillomavirus is a major cause of cervical cancer. Since the first identification (circa 1980) of HPV, research has moved at a staggering pace to the point where an anti-viral vaccine has been produced.

The Past: The research in York has focused on the biology and structure of the HPV E2 protein, which acts to control the virus life cycle. After 8 years of research, we were able to make highly purified protein (the amount present in a million, million cells!) and generate highly specific antibodies against HPV E2, which have been supplied to many laboratories worldwide. In 2000 we published a unique 3D picture of part of this molecule, which provided new insights into its activity. The antibodies were used to monitor the presence of the E2 protein during cancer development.

The Present: One major consequence from the E2 structure was the hypothesis that the protein could dimerise at two different points in the molecule, to generate dimers of dimers, which in turn could result in the formation of loops in DNA. Dr Julie Burns, in collaboration with scientists at the University of Nottingham, has recently been able to visualise these loops using a new technique known as Atomic Force Microscopy. Normal E2 protein causes the DNA to form circles, held together by the E2 protein. When we also change several critical amino acids in the protein or when we delete the segment of E2 responsible for the second dimerisation, there are no loops, but the DNA is still decorated E2 protein attached at specific binding sites.

The Future: As the HPV research winds down in York, we are seeking our final answers to the riddle of E2 function. Unlike prostate cancer, where the major risks are being male and getting old, we do know the major cause of cervical cancer and now have a means to prevent the tumour and even to treat it.

YCR p53 Research Group

P53 - The bodys natural defence against cancer. P53 is a naturally occurring protein, present in all tissues of the human body. It is inherited through the p53 gene and is passed on during cell division. All cells express p53 and it acts to suppress the development of cancer. It is classified as a tumour suppressor.
P53 functions by sensing danger and causing genetically damaged cells to stop growing. Alternatively, the cells are programmed to die. Both responses safeguard against passing on damaged genes to daughter cells. In this way p53 helps protect against accumulation of genetic damage in human tissues. This is of utmost importance because genetic damage leads progressively to tumour development and cancer.

The huge importance of p53 is evident when its function is lost (due, for example, to damage of the p53 gene). Over half human cancers are deficient for p53. In some cases loss of p53 function is preventable. Carcinogens present in cigarette smoke directly attack the p53 gene and lead to lung cancer. Ultra-violet irradiation also damages p53 with the development of skin cancer. We should protect our protector by not smoking cigarettes and by taking care when enjoying the sun. In humans the inheritance of a defective p53 gene results in 50% incidence of cancer before the age of 30 years. Working with human cells in culture we are now investigating why loss of only one of the two p53 genes has such a devastating effect.

In order to understand and to exploit p53 in the battle against cancer we have aimed to resolve the molecular structure of the p53 protein. In collaboration we have resolved the molecular structure of the interface between p53 and one of its partner proteins called RPA. This work, which took several years to complete, is now submitted for publication. Why are such molecular structures important? Once the folding of a protein molecule into its 3D structure is understood, and the shapes and surfaces necessary for its function are identified, it becomes possible to influence its functioning within the cell. In the case of p53 the future holds promise for modulating structure and function in favour of cancer cell killing.

At another level we have examined the p53 protein within living cells and analysed the molecular partners which come into play during the p53 response to cellular damage. We have discovered that p53 protein is associated with nuclear F-actin. F-actin represents a part of the cells cytoskeletal system which is able to move molecules and larger structures to specific locations within the cell. The cytoskeleton is emerging as a crucial regulator of diverse cellular processes. The success of our project would not have been possible without the expertise and collaborations based at the University of Cambridge, at the MRC Laboratory of Molecular Biology (also in Cambridge), and our own expertise here in York.

Approximately half our work at York is carried out in-house, made possible by YCR funding for sophisticated equipment. One of our discoveries has revealed that endogenous p53 can influence genetic structures within the nucleus of cells. Other projects involve the regulation of p53 function and include genetic engineering and protein expression systems.

It is remarkable and reassuring to note that our chosen experimental models are not only yielding results important in their own right, but are also generating information which gives a consistent picture despite the diversity of our approaches. Results from different projects can be cross-correlated to provide in-depth understanding of the regulation and functioning of the p53 tumour suppressor. From such understanding novel approaches to anti-cancer therapy will follow.

A major arm of our research at York holds promise for more rapid development towards novel anti-cancer therapeutics and is based upon a newly discovered phenomenon called RNA interference (or RNAi for short). First discovered in petunias, the process of RNAi allows for selective silencing of individual genes within living cells and operates with exquisite precision. Our first RNAi project aimed to silence cancer-causing genes in human cervical cancer cells. The treated cancer cells died whilst non-cancer cells, treated identically, were unaffected. Cervical cancer is caused by the human papilloma virus and the chosen target for RNAi was a viral gene. We are also employing RNAi to dissect death pathways involving the p53 protein. Present and future research will continue to identify genes necessary for cancer cell survival but dispensable for non-cancer cells. Once the Achilles heel of cancer is identified anti-cancer therapies that are non-toxic to normal healthy tissues of the body can be developed. For development to the clinic the agents that induce RNAi have to be delivered to the patient. This is a major focus of research for pharmaceutical companies specialising in RNAi-based therapeutics. At York we have developed a method for topical induction of RNAi.

We continue to publish our work in high-ranking scientific journals. In 2004 we were especially gratified when the journal Nature selected one of our publications for a News and Views article. In addition our RNAi research continues to attract world-wide public and professional interest.

Since its beginnings in 1991 many young scientists have passed through the YCR P53 Research Laboratory. All are progressing very well in their chosen careers and some have achieved high international profiles in cancer research. Each member of our team plays their own key part in the progress and success of our research. All are highly motivated and selfless in their dedication to cancer research.