YCR research 2002/3

University of Bradford
YCR Laboratory of Drug Design

The past year has seen a consolidation of the YCR Laboratory of Drug Design with the Cancer Research Unit to form the united Tom Connors Cancer Research Centre at the University of Bradford. This union is in recognition of the late Professor Tom Connors, who played a steering role in both the clinical development of new chemotherapeutic agents in the UK and the founding of the two Bradford teams.

The YCR laboratory has built upon its early success in using state-of-the-art methods such as computer-assisted molecular modeling and biocalorimetry to refine and simplify the drug design and evaluation process. Focus has been maintained upon the development of powerful drugs that are only activated or 'switched on' within a tumour, but show no adverse effects (i.e. remain 'switched off') in normal tissues. Such approaches will reduce the burden to patients by reducing the level of administered (pro)drug whilst maintaining anti-tumour efficacy.

Studies of structure and function for cancer proteins and DNA/RNA continue to provide impetus for the diverse research programmes, where novel anti-cancer drugs are rationally designed to interact at the molecular level. Professor Terry Jenkins and his YCR-supported team have strong linkages with many research groups and collaborate with major UK cancer researchers at the vital clinical interface.

University of Hull
Centre for Magnetic Resonance Investigations

Work continues on the advancement of models that reflect patho-physiological processes, on the development and implementation of spectroscopic imaging and on accurate measurement of T2* relaxation times from which tissue oxygenation can be inferred. These techniques are used extensively in our ongoing programs.

Classification of breast masses and determination of tumour extent by MRI for appropriate and cost effective management of women scheduled for wide local excision, forms the basis of a Hull based multi-centre study. Neoadjuvant chemotherapy for locally advanced breast cancer is used to facilitate conserving surgery and improve prognosis. However there is a pressing need for early evaluation of treatment response and the roles of DCE-MRI, proton MRS and water ADC are being evaluated against overall tumour volume response, markers of apoptosis and surgical findings.

The introduction of inversely planned intensity modulated radiotherapy that allows sculpting of the dose distribution and boost dose escalation, relies on accurate tumour localization. Work is ongoing to amalgamate CT and MR images allowing electron density, metabolite concentrations, tumour vascularity, and functional imaging to be incorporated in to the planning process.

In gynaecological malignancies MR staging accuracy is compared with surgical findings and subsequent patient management. The team is developing proton spectroscopic techniques to determine the concentration of choline and other metabolites in ovarian cyst fluid and solid tissue elements to enhance lesion discrimination and monitor treatment response.

University of Leeds
Leeds PDT Group

YCR makes contributions to a great many aspects of cancer research, but it is especially pleasing to be able to report that an initiative started by YCR has now led to two drugs going into pharmaceutical development. The Leeds photodynamic therapy (PDT) group was founded with substantial YCR support almost 15 years ago. Since that time, YCR has continued to be the major funder of the group, which became the University of Leeds Centre for Photobiology and Photodynamic Therapy some 8 years ago, with some 35 scientists and clinicians working to develop new PDT drugs.

The Centre has achieved a global reputation in this field, with the discovery of families of new drugs for this emerging therapy. With YCR as a participant, a new company, Photopharmica limited, was formed to commercialise these discoveries and move the drugs on through the drug development process. It is planned to use one of the drugs to treat early cancer and pre-cancerous conditions and the other to treat bacterial and other infections.

Photopharmica obtained its first seed corn investment funding during 2002 and as this report went to press, the Company has announced a major new multi-million pound investment, through which patients will start to benefit from these drugs within 18 months. YCR will continue to have an interest in Photopharmica as our years of investment in the research begin to bear fruit for the general benefit of patients.

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

In Sheffield, the Yorkshire Cancer Research endowments underpin research being undertaken within the Institute for Cancer Studies and Academic Unit of Clinical Oncology.

On the laboratory side, Professor Mark Meuth is expanding research in cancer genetics and genetic epidemiology. From the clinical point-of-view Professor Rob Coleman has ensured that the Clinical Trials Centre has taken a major role within the National Cancer Research Network. Professor Penella Woll has recently joined the team from Nottingham; she has an international reputation in clinical and translational research in lung cancer.These, together with collaborative links to basic science and NHS, have resulted in 'cancer studies' being highly rated in the recent University Research Assessment Exercise and accorded priority status in both University and NHS research strategy.

University of York
The YCR Cancer Research Unit

The last 12 months has seen some radical changes in the YCR Cancer Research Unit at the University of York. Prof Maitland's team occupied the new YCR funded laboratories into the new Biology Centre in which purpose-designed laboratories were provided at a total cost of some £700,000 by YCR in July and despite a number of construction problems which set back work for some time, the laboratory is now fully equipped and operational. It provides up to the minute facilities for gene cloning and the generation of gene therapy vectors as well as culture and analysis of human prostate samples. The effectiveness of the laboratory is assisted by the large and well equipped Technology Facility included in the new building, which opened officially in July 2003. Credit for the smoothness of the move to the new Cancer Research Unit must be given to Michelle Mounter and Sam Hansford. Their hard work and organisation ensured that the science was ready to go on day one.

The Research Team in the Cancer Research Unit was augmented by the award of a National Cancer Research Institute Centre of Excellence Grant for Prostate Cancer Research. This funds two additional scientists in the Cancer Research Unit to work on projects closely related to those funded by Yorkshire Cancer Research.

Scientifically the highlights of the year centred on the discovery of new models of prostate cancer (which obviate the need for animals and experimentation on human tissues). First reports of these have been published in widely read international journals. The emphasis now is to exploit these models to improve our understanding and then design new therapies to attack the cancer cells themselves.

The provision of these brand new state-of-art laboratories will provide a new impetus to research in York into both prostate and cervical cancer.

University of York
YCR p53 Research Group

Part of the current research aims to silence cancer-causing genes using a new technique called RNA interference. Professor Milner's group has succeeded in blocking the expression of viral genes responsible for the development of human cervical cancer. The new anti-viral treatment causes the cancer cells to die when grown in culture in the laboratory. Remarkably, normal cells appear to be completely unaffected by the same treatment. Thus they have developed a novel approach to treat cervical cancer that seems selectively to kill the cancer cells. The same new methodology is now being applied to silence other cancer-causing genes.

In parallel with the above research the group is also developing new techniques to visualize events within the cell and which relate to cancer. For example, DNA damage within the cell nucleus predisposes towards cancerous growth if the damage if not detected and repaired. These two crucial functions are performed by protein complexes (factories) which are mobilized in response to DNA-damaging agents such as ultra-violet light from the sun. It has been discovered that the p53 protein (the body's natural defence against cancer) plays a central role in relaxing the highly structured assembly of chromatin. In so doing p53 makes sites of DNA damage in the chromatin accessible to the repair factories in the cell.