The research is directed and supervised by a team of scientists primarily based here in Exeter. This team includes Dr Jackie Whatmore, a cell biologist, Dr Paul Eggleton, a biochemist and Dr Nick Gutowski a consultant neurologist at the Royal Devon and Exeter Healthcare Trust all of whom are researchers with the Peninsula Medical School in Exeter. In addition, Professor Chris Moody is an organic chemist who despite recently leaving Exeter for a prestigious new post in Nottingham continues to liaise closely with the Exeter researchers to advance the research funded by FORCE.
FORCE continues to fund the on going programme of Cancer Research in Exeter that has been jointly carried out in the Cell Biology laboratories, Peninsula Medical School and the School of Chemistry, University of Exeter. This research has expanded and now includes a doctoral student in Chemistry (Marie Colucci), and a doctoral student (Lesley Maskell) and a part-time research technician (Selina McHarg) at the Peninsula Medical School.
Exciting research continues in three main areas:
1. Angiogenesis inhibitors.
A major part of the work continues to be investigating possible inhibitors of tumour growth. We aim to do this by targeting the process of new blood vessel formation (angiogenesis). Angiogenesis is essential for tumour growth and metastasis because a tumour can not grow larger if new blood vessels do not form to provide a blood supply. Therefore, if angiogenesis can be inhibited, then it should prevent tumour growth. A major body of work has concentrated on developing and testing both new drugs and chemical systems to target these drugs to solid tumours.
Work in this area has expanded enormously over the years. Initially it was recognised that in order to test the effectiveness of anti-angiogenesis drugs it was vital that an appropriate cell based model be established. Therefore, initial work focussed on researching methods used by others and setting up such an assay in Exeter. This assay has subsequently allowed the testing of an ever increasing range of anti-angiogenic drugs and delivery systems and importantly has also attracted the interest of other researchers wishing to collaborate and thus expand the cancer research in Exeter.
There are now three major projects being carried out in this area:
(i)
The continuing project to develop, make and test possible anti-angiogenic drugs attached to special delivery drugs. The major aim of our research has been to develop new selective chemotherapeutic agents with potent effects on tumour cells, but which are (ideally) harmless to healthy cells. This is achieved by designing pro-drugs (i.e. an active drug attached to a "delivery" molecule) that are inactive until broken down within tumours to release the active agents. A range of both free drugs, delivery |
systems and drugs attached to delivery systems have been synthesized and tested for anti-angiogenic activity and cytotoxicity. One paper has now been published on this work and the second phase of this work is currently being written up for publication. |
 |
(ii)
The second project in this area is an exciting collaboration with Dr Mike Shipman, who was previously in the School of Chemistry, University of Exeter and who is now at the University of Warwick. In spite of the move the collaboration continues and has resulted in publication in an international journal. The project involves the biological testing of the bacterially produced factors, |
luminacins, which are reported to have anti-angiogenic activity. It is not known how these drugs work and it is hoped that studies will progress to examine this problem. This collaboration has lead to a successful grant application from the Engineering and Physical Sciences Research Council that funds a PhD student to work in Warwick and Exeter. |
(iii)
| To examine the anti-angiogenic potential of a protein called calreticulin. The project is in collaboration with two new members of the Peninsula Medical School - Drs Paul Eggleton and Philip Young. Calreticulin is an abundant protein secreted from cells and has been observed to inhibit angiogenesis in a cell based assay and to inhibit tumour growth in animal models. |
Since this is a naturally occurring protein it is hoped that it will have minimal cytotoxicity. A small grant has been obtained to further this project and examine which region of the calreticulin protein is required for its anti-angiogenic activity and also its mode of action using our in vitro assay. It is hoped that ]the preliminary data will lead to further grant applications in this area. |
2. The biological processes involved in brain metastasis formation.
Brain metastases arising from lung tumours are relatively frequent. In order for a metastasis to form the tumour cells need to cross the endothelia! cells lining blood vessels and invade the brain, coming into contact with astrocytes (the main supporting cells of the brain) and then induce angiogenesis in endothelial cells to supply the growing tumour as described above. The specific biological processes that allow metastases to form are largely unknown. One of the ways in which cells communicate with each other and induce changes in the surrounding tissue is by secreting chemical messengers. Thus, this research involves investigating factors released from cultured lung tumour cells and examining their effect on both brain astrocytes and endothelial cells to see if the lung tumour cells induce changes in these cells. Excitingly it appears that the lung tumour cells do secrete factors which influence astrocytes and the identity of these factors is currently being investigated. Clearly if these factors are essential for metastasis formation then targeting these factors may be of therapeutic benefit. The ability of lung tumour cells to induce angiogenesis is also currently being carried out using our established assay.
3. Tumour development and phospholipase
Phospholipase D is an enzyme that is increasingly being recognised as being very important in cells. This project examines how the action of phospholipase D is altered in tumour cells. This work has formed a part time MPhil and has also attracted external funding.
The FORCE-funded research continues to be extremely productive. This research has been published internationally and widely presented at conferences both home and abroad. It has lead to considerable scientific collaboration, to the attraction of further external funding, and probably most importantly, through the research studentships funded by FORCE, provided vital training for cancer researchers of the future.
FORCE continues to fund the on going programme of Cancer Research in Exeter that has been jointly carried out in the Cell Biology laboratories, Peninsula Medical School and the School of Chemistry, University of Exeter. This research has expanded and now includes a doctoral student in Chemistry (Marie Colucci), and a doctoral student (Lesley Maskell) and a part-time research technician (Selina McHarg) at the Peninsula Medical School.