Identifying more effective ways to kill Ewing’s sarcoma family of tumours 

 Dr Helen Payne is a postdoctoral research fellow who joined the Candlelighters Children’s Cancer Research Group based in the Leeds Institute of Molecular Medicine, part of the University of Leeds at St James’s University Hospital in January 2009. She is married to a civil engineer, with a daughter who is 3 years old. Helen graduated from Durham University in 2002 with a degree in Biomedical Sciences. She continued her studies at Durham to gain a PhD in neuroscience in 2006 where she continued to work as a postgraduate researcher before joining the Candlelighters group in Leeds. Helen’s work has focussed on learning more about how receptors work in different disease processes. These are structures which sit in or on the outside walls of cells, and pass messages to the cell which may cause it to multiply, alter the way it works, or even cause it to switch off and die.

Helen is currently working to identify new strategies to kill cells of the Ewing’s sarcoma family of tumours (ESFT) that might be exploited to improve future treatment and outcome for those diagnosed with this aggressive cancer. In previous studies the group in Leeds have shown that fenretinide rapidly kills ESFT cells but importantly not normal cells, making it less likely to cause the common side effects of chemotherapy and thus making it a potentially attractive new agent. Although fenretinide based treatments are currently being tested in clinical trials, we believe that by understanding exactly how fenretinide initiates cell death in cancer cells specifically it will be possible to develop even more effective treatments, whilst minimising any harmful side effects, by fine tuning fenretinide-like drugs.

In her studies, Helen has shown that the ability of fenretinide to kill ESFT cells is increased in cells that have lots of HPR1* on the outside of the cell and decreased when levels of HPR1 are reduced. Furthermore Helen has shown that if ESFT cells are exposed to low concentrations of fenretinide, they increase their levels of HPR1 on the outside of the cell. These observations indicate that this receptor may play a role in the response of the ESFT cell to fenretinide. Helen is now examining whether this effect of HPR1 is specific to cancer cells.

How effective fenretinide is in causing cell death has been shown to be altered by the presence of specific proteins found in plasma. Helen has shown that these proteins can decrease the uptake of fenretinide into ESFT cells. This supports the hypothesis that plasma proteins may change the activity of fenretinide, and this may happen by the proteins, the fenretinide, and the HPR1 receptor all binding together in a specific way. Because of the potential importance of this fenretinide-HPR1-plasma protein complex in causing and modulating cancer cell death, a clinical research fellow (Dr Shireen Gopaul) has now joined the team to work on this. The activity of the group is further strengthened by two students working on creating completely new fenretinide-like agents, and the regulation of the ESFT cells which become metastatic, which are frequently responsible for the disease relapsing.

In these studies we are collaborating with Professor Colin Fishwick and Dr Richard Foster from the Department of Chemistry here at the University of Leeds. Colin and Richard are able to design and synthesise novel molecules that allow us to study the biological response of ESFT cells to maximum effect. Through these studies we will increase understanding of the mechanisms by which fenretinide causes cell death, with the goal of identifying targets for the development of novel drugs or combinations. Through these studies we hope to discover markers that could be measured in patient samples and used to select the patients who would benefit most from treatment with fenretinide or related molecules that interfere with this cell death pathway.

To improve the quality and speed of the experiments to measure the amount of cell death in the ESFT cells, Helen is using the Vi-CELL ® automated viable cell counter. Candlelighters funded the purchase of this important instrument for the Candlelighters Children’s Cancer Research Group in 2008. The research of many members of the group benefit from this equipment, as by using the Vi-CELL ® we can rapidly and reliably evaluate the efficiency with which molecules kill cells, so that we can prioritise molecules and strategies for further study.

Thank you to all the Candlelighters who have made this research possible, and for your continued support of and commitment to the Candlelighters Children’s Cancer Research Group.

Professor Susan Burchill, Scientific Director Candlelighters Laboratory and Dr. Helen Payne - Candlelighter’s Post Doctoral Research Fellow.

Glossary
Plasma - the liquid part of blood
Metastatic - spreading of a cancer from the original tumour to other parts of the body by means of tiny clumps of cells transported by the blood or lymph
HPR1 - a pseudonym to protect the identity of the receptor for the purpose of intellectual property