YCR research 2005/6

University of Bradford
Institute of Cancer Therapeutics

YCR Medicinal Chemistry Section of the Institute of Cancer Therapeutics

A new programme to discover and develop new cancer therapeutics is underway and supported by YCR. Funding for four senior research positions has enabled the recruitment of medicinal chemists who are progressing several new areas of drug discovery. The YCR funding is focused to create a Medicinal Chemistry Section within the Institute, directed by Professor Laurence Patterson, YCR programme grant holder. The Section Leader is Dr Kamyar Afarinkia, who has day to day oversight of the medicinal chemistry facility and also leads a team of medicinal chemists, and two further team leaders, Dr Robert Falconer and Dr Klaus Pors. As well as direct responsibility for conducting research each team leader is responsible for identifying further funding to populate their chemistry teams. In the past year the YCR-sponsored team leaders have secured funding from the EPSRC, AICR and biotech industry which is collectively supporting six further medicinal chemists.

YCR Proteomic Section of the Institute of Cancer Therapeutics

The YCR programme grant is also funding a Mass Spectrometry and Proteomics Section within the Institute. Dr Chris Sutton is Section Leader and under Professor Patterson's guidance is building a team to deliver a state-of-the-art service to the medicines discovery needs. Proteomics is a way of identifying and measuring tens, hundreds or even thousands of proteins simultaneously. This is important because of the 300,000 proteins present in cells only a small percentage are different in cancer and it would be impossible without proteomics to advance our understanding of them quickly. The Proteomics facility was established in January 2006 with the commissioning of the £750,000 equipment that was partly funded through generous support from YCR. The facility will play an increasingly important part of our drug target investigations.

Tumour-activated medicines and anti-metastatic agents

A major obstacle in the treatment of cancer is the lack of selective killing of cancer cells with currently used cancer medicines, which generally damage normal tissues and lead to severe side effects. The ultimate aim of this project is to develop a cancer medicine that is harmless to the body but will help to eradicate the tumour or stop it spreading to other areas of the body. This will be achieved by using the cancer cell to convert a drug from something inactive to a powerful cell killing agent.

Certain enzymes are found to have a higher presence in cancer cells compared with the surrounding normal tissue. This will be exploited in two ways. Firstly by essentially hijacking these enzymes in the tumour to produce an agent that is highly damaging to the cancer cell DNA or blood supply that feeds the tumour cells. It is envisaged that agents will be administered to patients that produce no side effects commonly associated with current therapies, but when reaching the tumour will be converted to a product that causes the demise of the tumour. The second approach is to inhibit an enzyme that encourages cancer cells to detach from the mass of the cancer and migrate to other parts of the body to grow as secondary cancer, a process known as metastasis.

In the last year we have established the YCR-funded teams within the Institute as described above and have begun the design and chemical synthesis of some new compounds that are being measured in the laboratory for their activity against cancers. The teams work closely with colleagues funded by Cancer Research UK in a joint venture of drug discovery.

Tumour matrix metalloproteinase-activated agents

Matrix metalloproteinases are a family of enzymes that are found in tumour tissue to enable the tumour to invade and grow within the organ it is associated with. One YCR-funded project is using this type of enzyme to selectively release an agent that will disrupt tumour blood supply with the purpose of starving the growth of the tumour. New agents have been synthesised by the YCR medicinal chemists and are in the process of being tested against tumours that are known to highly express matrix metalloproteinases. Results generated over the past funding year are promising with selective release of the active agent in the tumour whilst sparing normal tissue. A screening process is under development to select the most useful agents.

Tumour Cytochrome P450-activated agents

Cytochrome P450 is a family of enzymes that normally work to render harmless drugs and other compounds taken into the body. Cytochrome P450 family members also produce steroids and other molecules that help the body to grow and survive. For reasons that are not yet clear some cytochrome P450 family members are highly expressed in tumour cells. Because cytochrome P450 can metabolise drugs we have designed new agents that can be converted to potent anticancer compounds by certain types of this enzyme. Our new compounds are inactive in the body until metabolised by CYP1A1, one example of a cytochrome P450 that is highly expressed in some tumours. Studies are ongoing to establish methods to screen for the best agents in terms of selectivity of activation and potency once converted in the tumour.

Antimetastatic agents

Strategies are under development to design and synthesise new agents that will serve to block or discourage tumour cells from detaching from the cancer and lodging in other parts of the body to grow into new tumours. This process, called metastasis, is the main reason for treatment failure and death of cancer patients. Certain types of cancer, including small cell lung cancer, non-small cell lung cancer, neuroblastoma and pancreatic cancer have special sugars on their cell surface. Disruption of the production of these sugars may prevent such cancer cells from detaching from the primary tumour and hence discourage metastatic spread. The detail of our approach will be described in future bulletins from the Institute of Cancer Therapeutics.

University of Hull
Centre for Magnetic Resonance Investigations

Recent advances in Magnetic Resonance (MR) technology have resulted in the manufacture of whole-body scanners with stronger magnetic fields. A 3.0 Tesla whole body scanner was installed at the Centre for Magnetic Resonance Investigations at the University of Hull in 2004, the first of its type to be installed in the UK. This increased field strength allows us to produce better quality images which contain more detail and also gives us the ability to acquire information about how different organs function, in clinically acceptable scan times.

Breast patients with large tumours usually receive chemotherapy before surgery, termed 'neoadjuvant chemotherapy'. The aim is to reduce the size of the tumour so that surgery is less disfiguring and to destroy any cancer cells that may be elsewhere in the body. There are many different types of chemotherapy, and a course normally lasts for 3-6 months, and produces many side-effects; the most common being sickness, low blood counts and tiredness. Currently, there is no way of telling if the chemotherapy has worked until the end of treatment. About 35% of patients do not respond to chemotherapy. In this patient group chemotherapy has been wasted, since it has not improved the patient's condition, has reduced their quality of life, has stopped them getting more effective therapy (and so may have reduced their expected life span), and has been expensive. Research at the Centre for Magnetic Resonance Investigations has identified changes in breast cancers that occur before they start to shrink. These changes can be detected by scanning the patient using advanced MRI techniques.

The breast research program currently investigates the local extent of tumour and the ability of advanced MR techniques to predict how patients will respond to treatment and subsequently to monitor the response of the breast cancer to chemotherapy. The techniques used include examining parameters reflecting the nature of the blood supply and the extent of oxygenation of tumour tissue, the chemicals present in the tumour (MR spectroscopy), measurement of the random movement of water molecules which is altered in disease states, and the texture of tumour tissue. Preliminary work indicates that several of these parameters can predict response of locally advanced breast cancer to neoadjuvant chemotherapy.

If MRI is able to predict the death of cancer cells, caused by many different types of chemotherapy, then it could be used as a standard technology for the early assessment of response to neoadjuvant chemotherapy. Ideally, patients would only have a few days of chemotherapy before knowing whether or not it was effective. The main research outcome is to determine if this novel way of using MRI can tell whether chemotherapy will be successful in individual patients at an early stage of their treatment.

The development of diagnostic and imaging techniques is a key national policy thrust, since the accuracy of diagnosing tumours and other conditions is crucial to the cost effective management of patients. However, MR imaging is an expensive resource, and both radiographers and radiologists are in short supply. This impedes the full utilisation of MR imaging and limits its use in larger, more powerful clinical trials. As a consequence the CMRI is working towards establishing fully automated analysis of the MR data. This would allow us to set up a large multi-centre MR trial. This should allow breast chemotherapy patients to receive a pre-programmed MR scan early during treatment, which could be read automatically either locally or centrally, using a standard software package. This would significantly reduce the burden on staff, and would allow a trial to reach completion more rapidly. Staff at the CMRI are actively working to set up a national multi-centre study using these techniques.

Prostate cancer is one of the commonest forms of malignancy in men with an incident rate that has risen dramatically over the last few years, primarily due to the increasing prevalence in the under 65 age group. MR imaging and assessment of the chemical composition of prostate tissue is being used in the CMRI to determine the extent of tumour present potentially allowing better clinical management of prostate cancer sufferers. Information regarding the movement of water within tissues, the blood flow within the prostatic gland, and the concentration of chemicals which are more typically present in malignant compared to benign tissue are being compared with specimens obtained at surgery. The utility of this additional information will be compared in the future with survival curves to study the benefits of MR in predicting "disease free" survival.

It is now well recognised that neither computed tomography nor ultrasound scanning are as accurate as MRI in the evaluation of cancer of the pelvis in women. In this centre MR is used to distinguish between benign and cancerous pelvic masses and where cancer is present to determine the extent of disease so that the treatment can be tailored to each individual. Patients with tumours of the cervix and the womb are also being assessed to determine the extent of infiltration of the overlying tissues. The overall diagnostic accuracy of MR imaging of gynaecological malignancies in our hands is 93%. For advanced cancer, the role of 3T imaging to assess response to chemotherapy is being investigated.

In patients with brain tumours information from imaging, spectroscopy and functional studies of the brain is being combined to better delineate the tumour volume present. This work aims to identify areas in which greater tumour kill rates could be achieved, if an additional "boost" dose was applied. Such techniques require careful quality assurance, advanced software programming and comparison with conventional techniques. Verification of the proposed radiotherapy plans is under investigation using BANG gels developed in association with the University of York, which change composition and hence MR appearance on exposure to radiotherapy.

University of Leeds

Firstly our thanks need to be extended to Yorkshire Cancer Research for their contribution to our new building that has provided state of the art facilities for us to work in. This has made a huge difference bringing together all of our researchers under one roof in a very pleasant environment.

This year has been very successful with the results of the MRC CR07 trial being presented as a plenary presentation at the main meeting at ASCO, the 3 year disease free survival clinical results of the MRC Clasicc trial being submitted for publication and the publication of two important papers highlighting the need for change in how we perform the abdomino-perineal excision operation. We have also been planning three new trials ARISOTLE a rectal cancer trial comparing different types of preoperative chemoradiotherapy, the ENROL trial comparing laparoscopic colorectal cancer surgery with standard post operative management vs rapid mobilisation and early discharge from hospital and ENACT which compares standard management with preoperative chemotherapy for colonic cancer.

Our unit will undertake the pathology for these national trials should they be successful in winning funding. The national training programme for rectal cancer funded by the Department of Health is coming to an end and by the end of the year we will have trained 200 colorectal cancer teams and with David Forman from NYCRIS we are auditing the benefits of this nationally. Initial results look very promising. This is important as there is no point in making advances if we cannot introduce them into clinical treatment.

Building on this we are also creating for the first time a national database of colorectal cancer operations and outcomes that we hope will enable us to follow trends over time and assess the impact of interventions. This should include everyone in England undergoing an operation for colorectal cancer.

Locally we have been looking at the frequency of loss of anal sphincters in Yorkshire to see if we can reduce the frequency of stoma formation. We believe we have generated evidence that much could be done in this area. We continue to work on the molecular pathology of Quasar and Focus1, Focus 2 and Picolo, the last three in association with Matt Seymour's CRUK group. We are also currently building a retrospective collection of 2000 cases of colorectal cancer to allow us to rapidly test significant new molecules for their clinical value in Leeds patients.

We have also established a cadaveric tissue bank (http://www.gift.leeds.ac.uk/) funded by research grants and pharmaceutical companies to collect cancer tissue for research. For this we received a national award. This will facilitate our own research and that of others as well as allowing cancer victims a way of helping to fight back against their disease.

MRC CR07 recruited 1350 patients and compared preoperative short course radiotherapy with postoperative chemoradiotherapy for margin positive patients. Included within it is a comprehensive pathology protocol and very importantly an assessment of the completeness of the surgical excision but also a pathologist's assessment of the quality of surgery. The results were very exciting. Not only did it show that short course radiotherapy reduced by half the number of local recurrences and significantly extended patient survival but it revealed that the effects of radiotherapy were closely linked to the quality of surgery. The best possible surgery and radiotherapy led to the almost complete abolition of local recurrence changing outcomes from 19% when poor surgery and no radiotherapy occurred to 1% when good surgery took place and radiotherapy was received. The pathological judgement of quality of surgery also predicted 3-year disease free survival. These results are exiting as they show the way to completely avoid local recurrence in many patients with rectal cancer.

MRC Clasicc that recruited 794 patients compared laparosopic colorectal cancer surgery with open surgery and confirmed not only the safety of colonic surgery but also rectal surgery using such techniques. We were able to confirm yet again the importance of the pathological prediction of complete resection of the rectal cancers with 68% vs 27% alive at 3 years depending on margin status. Interestingly we were not able to demonstrate the same effect in the right colon, the first time this has been investigated with clinical outcomes. Papers in the Annals of Surgery and Journal of Clinical Oncology described the problems we have found with surgery for abdomino-perineal excisions with the quality of surgery being found to be poorer than that for surgery higher in the rectum. We have described the issues and suggested that a different operative approach would be worthwhile. This wider excision in association with chemoradiotherapy should help to improve outcomes in this area.

This work was the subject of an invited presentation at GI ASCO in San Francisco. Current work in this area is the exploration of 3-dimensional photography to record the quality of surgery in rectal cancer, and work on the quality of surgery in colonic cancer which if proven would make a major contribution to reducing deaths in these patients. This is running in parallel with contributions from us to improving the quality of colonic cancer surgery at the Karolinska in Sweden where they have been convinced of the importance of this work.

On the molecular front we are continuing to analyse new targets with their ability to predict outcome using tissue microarrays and comparative genomic hybridisation. Expression studies on Duke's stage B colorectal cancers failed to predict outcome as effectively as good histopathology but we are involved in larger studies in this area using Taqman testing. We have initiated a study on the adenoma-carcinoma transition by high resolution CGH looking for new genes that might be involved at this interface.

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

The conversion of a normal cell to a cancer cell is a long and complex process that involves the accumulation of many genetic modifications. Cells have elaborate controls that prevent genetic changes, however many of these are lost during tumour development. The research objectives for the Institute for Cancer Studies are: 1) to understand how cells respond to agents that damage the genetic material (i.e. DNA) and to resolve how these responses are altered in tumour cells; 2) to exploit the alterations of cellular response to these DNA-damaging agents to produce more effective targeted therapies; and 3) to establish how inherited alterations of the cellular response determine individual risk of developing cancer or how individuals respond to therapy.

Considerable progress towards these goals has been achieved over the last year. In particular, Thomas Helleday's group published a paper in Nature that attracted international attention. Thomas and his co-workers discovered that breast cancers in patients showing a strong family predisposition as a result of an inherited mutation of BRCA2 are acutely sensitive to an inhibitor of a DNA repair enzyme called PARP-1. Notably the cancerous cells in these patients are exquisitely sensitive to this agent while normal cells are unaffected. Thus the inhibitors can be used as chemotherapeutic agents to specifically treat this type of tumour and as a chemo-preventive agent to eliminate early precancerous lesions so that tumours never develop. This novel therapy is potentially applicable to the 5% of breast cancer patients who carry BRCA1 or 2 mutations and up to 10% of sporadic tumours that acquire alterations of these genes. Phase 1 trials of this new therapy have been completed successfully and Phase 2 trials are underway.

A collaborative project between Professor Meuth and Dr Helleday has revealed another potential novel therapy for the treatment of some forms of colon cancer. They have found that an inhibitor of DNA replication can significantly enhance the tumour killing effects of a drug (irinotecan) widely used in the treatment of colon cancer. They have also shown that this combination therapy is most effective when targeted to a specific type of colon cancer that can be identified by genetic tests. This work has been submitted for publication. In addition Professor Meuth's group has discovered a new approach for improving the effectiveness of some chemotherapeutic agents (Rodriguez & Meuth, Mol. Biol. Cell, 2006). A problem with some drugs is that they do not kill tumour cells, only slow their growth. Professor Meuth's group has found that the inhibition of a set of "DNA damage response genes" can dramatically enhance the killing of tumour cells in response to some types of chemotherapeutic agents (including irintotecan). Future work in Professor Meuth's and Dr. Helleday's laboratories is directed at understanding the mechanisms underlying these effects and in identifying new targets that can be exploited to improve the treatment of cancer.

Work in Dr Angie Cox's laboratory aims to understand the effect of inherited alterations of DNA damage response genes in cancer risk and response to therapy. In the previous year she reported a novel alteration that reduced the risk of breast cancer. This work was followed up by an international consortium of laboratories that tested the effect of this alteration in populations around the world. This study revealed that the alteration discovered by Dr Cox's group is the only such marker that reliably predicts an individual's risk to this form of cancer. This comprehensive study has been submitted for publication in Nature Genetics. Further work in Dr Cox's laboratory is directed at identifying other such genes that confer risk to breast, prostate or colon cancer and to understand the mechanisms underlying this enhanced risk.

Other research in the Institute includes Jim Catto's work on the effect of gene silencing on the development of bladder cancer and Cyril Sanders' work on basic mechanisms controlling the initiation of DNA synthesis.

This year has also seen the award of a number of honours and awards to Thomas Helleday and the establishment of a number of national and international collaborations with all researchers in the Institute. In addition two new members of the Institute were appointed. Thierry Nouspikel, who did his training at the University of Geneva and Stanford University in the USA, joined us in January. Kerstin MacClean trained at the University of London and the St. Judes Children's Research Hospital in the USA and will join us in March 2007. All of these developments are indicators of the increasing international reputation of the Institute for Cancer Studies.

Aside from work being undertaken at the Institute other Sheffield researchers are undertaking exciting new projects supported by YCR. Hypoxic areas are a hallmark feature of tumours but are difficult to access and thus treat by conventional therapies due to poor vascular supply; Professor Claire Lewis and her colleagues are developing novel strategies for targeting gene therapies specifically to these sites. A problem with potential cancer vaccines is their low immunogenicity; Andy Heath's team is working on overcoming this by using conjugates of a monoclonal antibody CD40 to enhance immune anti-tumour responses. Professor Peter Andrews is investigating regulatory genes and malignant stem cells, particularly in the context of testicular germ cell tumours but hopefully to enhance our current knowledge of tumorigenesis and the development of novel therapies. Colby Eaton and others are working with a self protective protein (osteoprotegrin) produced by tumour cells, to see how it affects survival in prostate cancer. Professor Nicola Brown's team is majoring on studies to understand how proteins such as vascular endothelial growth factor and tissue factor modulate tumour angiogenesis. Jim Catto and colleagues are investigating another protein called Crumbs 2 as a putative new screening marker for tumour progression, and on the clinical front Wendy Tindale, with others, is assessing the use of a modified dual headed gamma camera/PET scanner to identify patients with non small cell lung cancer who are suitable for surgery. The main clinical research base (the Cancer Research Centre at Weston Park Hospital) under Professor Rob Coleman's leadership, continues its major involvement in clinical trials research.

University of York
The YCR Cancer Research Unit

Research in the YCR Cancer Research Unit at the University of York is now increasingly focused on human prostate cancer. There remains a pressing need for new prostate cancer therapies as the incidence of the disease begins to rise and the overall death rates, unlike those for breast cancer, remain static at best. In this respect safer and more targeted gene therapy offers a real alternative.

The gene therapy research in York has, in the last year, attracted substantial external funding from the European Union to support the gene therapy network which has been built up over the last 5-6 years. After a major award of 10 million Euros in 2005, we have now seen a further award which will result in an expansion of this area of work originally funded by Yorkshire Cancer Research.

The Pan-European network (known as GIANT) plans to start clinical trials later in 2006 or early 2007 once regulatory permission has been obtained.

Of more long-term importance in the study of our treatment of prostate cancer is the need to understand the mechanisms behind this common cancer in men, i.e. how and why do men develop prostate cancer. At present the major risk factors remain being a man and getting old. The attempts to define a dietary component in the cancer remain unsuccessful, although there is undoubtedly a role for diet, and the extreme variability of the tumour both in its appearance and in its response to therapy has confounded most common therapeutic approaches. In a paper and review published late in 2005 (Collins et al Cancer Research and Maitland & Collins, British Journal of Urology International), a new approach to the understanding of prostate cancer was defined. These two publications have excited an enormous amount of interest in the York-based research and could well change the approach of the medical community in the longer term to the treatment of prostate cancer.

Prostate cancer almost certainly derives from a stem cell in the prostate; the stem cells are not the equivalent of embryonic stem cells which can give rise to a whole embryo and indeed a human baby, but are specialised stem cells known as tissue stem cells. The tissue stem cells are long-lived and are 'primitive' in that they do not express many of the genes presently recognised as prostate-specific such as serum protein, prostate-specific antigen (PSA) which is often used for prostate cancer diagnosis. They are capable of transforming themselves into those characteristic cells making prostate products such as PSA under the influence of male sex hormones and other ancillary factors. The Cancer Research Unit has developed many of the most reliable laboratory culture models to study this development and we have been able to combine our expertise in stem cell isolation led by Dr Anne Collins with these in-vitro models after the return of Dr Shona Lang from maternity leave courtesy of a prestigious Wellcome Trust Career Development Fellowship. Our ability to grow and to isolate the stem cells now puts us in a strong position to identify first of all the nature of these stem cells, the triggers which may cause them to become a tumour and hopefully their Achilles' heel against which we can design cancer stem cell specific therapies.

Our pioneering studies in this area have now attracted further support from the UK National Cancer Research Institute as part of one of two Prostate Cancer Collaboratives or centres of excellence. In 2005 we also received major grant support from the US Department of Defense in the face of strong international competition.

The very existence of cancer stem cells in prostate and other cancers has been seriously questioned for many years but now with modern cell separation techniques in the facilities provided by Yorkshire Cancer Research in York we are able to work with these very rare cells which represent less than one in a thousand cells in any cancer. Paradoxically, in contrast to embryonic stem cell research, our aim is to derive new ways of killing cancer stem cells that result in a lasting and curative therapy for prostate cancers. This can be considered the tumour biology equivalent of killing weeds in the garden; remove the leaves and the weed grows back. However, kill the root, in this case the cancer stem cells, and the weed (cancer) will not return.

We believe that stem cell therapy will change the nature of cancer treatments. To this end we have sought patent protection for both the stem cell process and the many genes which could provide the new targets for anti-stem cell drugs. As with other YCR projects of this nature if a major pharmaceutical company were to exploit the stem cell targets patent protections would ensure that the profits from any commercial exploitation will be returned to YCR to help fund further research.

University of York
YCR p53 Research Group

P53 is a naturally occurring protein, present in all tissues of the human body. It is called a "tumour suppressor" because it prevents damaged cells from turning cancerous. For example, sunburn causes cellular damage to the cell's DNA and this can lead eventually to skin cancer. The p53 protein helps prevent this cancerous progression - but a better solution is to use sun block creams! This is because sometimes the ultraviolet light from the sun damages p53 itself, and damaged p53 can no longer function to protect against skin cancer and melanoma. Other events can knock out p53 function and over half all human cancers arise due to p53 deficiency.

Identification of other tumour suppressors
At York we are studying how p53 carries out its anti-cancer functions. We are also exploring other pathways that may serve to protect against cancer even when the p53 protein has been crippled. In other words we are seeking to identify other tumour suppressors in human cells and to understand how they function. This ongoing and future research aims to identify new markers for early cancer development. The research employs a process called RNA interference to silence the expression of individual target genes with exquisite selectivity. Gene silencing can be achieved without undue stress to living cells and thus we are able to investigate the regulation of cell survival operating under 'basal' non-stress conditions - more akin to the conditions in the living person, and avoiding experimental approaches that deliberately perturb and damage normal cell processes.

Identification of tumour promoters and selective killing of cancer cells
The regulation of cell division versus growth arrest is in continual balance and it is loss of this balance that drives the uncontrolled division of cancer cells. We have identified a key player in this regulation. It is called SIRT1. When normally expressed SIRT1 is good for us since SIRT1 is believed to be linked with longevity and good health. What's more, red wine (taken in moderation) enhances the function of SIRT1!

However, we have discovered that in cancer cells SIRT1 can also sustain the continued survival of cancerous growth. Importantly, we have also shown that inhibition of SIRT1 kills cancer cells whereas normal cells are unaffected. Thus SIRT1 represents a new target for selective anti-cancer therapy with few, if any, side effects. There are already many small molecule inhibitors of SIRT1 available and such drugs may include cancer-specific agents for future development.

Human cervical cancer
Our research into novel approaches to treat patients with cervical cancer continues. Vaccination may become hugely important for prevention of viral infection associated with cervical cancer development, however vaccination carries little benefit for those women who are already infected with the cancer-causing HPV virus. At York we have demonstrated that virally infected cancer cells can be killed by targetting the virus using RNA interference. Clinical collaboration with colleagues at Gateshead and also clinical links with Cardiff will investigate the feasibility of our novel approach to treat cervical cancer using topical application of anti-cancer agents. This particular project is now under the direction of Dr Ming Jiang and we are delighted to report that Dr Jiang has been short-listed and invited to apply for a prestigious senior research fellowship. This is due recognition for her outstanding research in this field.

P53 Research Group
Earlier this year Dr Carlos Rubbi left the group to take up a new position in Liverpool and we all wish him every success. Other current members of the group include Sally Raines, Julie Mercer, Dr Lorna Warnock, Dr Jack Ford, Cian Lych (PhD student), Dr Shafiq Ahmed, Rachel Adamson, Dan Kidd and personal assistant Julie Wainwright.

Prestigious Awards etc.

2005 European Molecular Biology Organisation (EMBO) funding award for an EMBO workshop to be held at the University of York, 2006. Co-applicants: Julian Hiscox, Carlos Rubbi and Jo Milner

EMBO Workshop, The Nucleolus: New Perspectives@ (co-organiser with Julian Hiscox and Carlos Rubbi). (2006)

Advisor and assessor Germany NGFN-2 national research funding and networking: member of international committee (2004-2006).

Some invited talks:

ESACT-UK 15th annual meeting. Keynote lecture (2005)

International symposium "P53 Resolutions" to celebrate Pr Wolfgang Deppert; Heinrich-Pette-Institut, Hamburg, Germany. (2005)

P53 Marathon, Ein Gedi, Israel. (2005)

P53 Workshop, New York USA 2006 - Heinrich-Pette-Institut Symposium 2006. To celebrate inauguration of new state of the art research building. Celebration symposium with 6 speakers.

Member Scientific Advisory Board, Benitec (Australia).