ProfessorJanet Shipley, Dr Zoe Walters, and Dr Edoardo Missiaglia
This project is using DNA sequencing technology to identify the genes which make rhabdomyosarcoma a particularly aggressive cancer. Alongside this, the project will look for genes which could be potential drug targets in the treatment of rhabdomyosarcoma.
Identification of direct downstream targets of the PAX3-FOXO1 and MYCN proteins in alveolar rhabdomyosarcoma as potential therapeutic targets
Deaths from cancer in children are, thankfully, rare. However, a leading cause of cancer related deaths in children is rhabdomyosarcoma, a soft tissue sarcoma. More effective treatments are urgently required and Dr Shipley proposed that increased understanding of the underlying molecular mechanisms in development and spread of rhabdomyosarcoma would yield new angles for investigation.
They found some new gene targets which look as if they could be promising ‘ways in’ to researching new treatments. Whilst there is still a very long way to go these are now being investigated further in their laboratory or will form the basis of future research.
In particular, she and her team were studying what can make rhabdomyosarcoma such an aggressive cancer.
About the Project
Genes produce messages which are usually converted into protein molecules. These then perform specific tasks inside the cells that make up the body.
In cancer, genes may produce too many, not enough or even the wrong messages. This inevitably disrupts previously normal cell growth and development. A key change in some rhabdomyosarcomas is a rearrangement of two genes, fusing one gene - PAX3 with another gene - FOXO1. This PAX3-FOXO1 fusion gene, and the aberrant protein it makes from its garbled message, is associated with rhabdomyosarcoma cells that are more likely to spread and spread faster.
Recent research has shown that this fusion gene is frequently found with increased copies of another gene - MYCN. MYCN and the PAX3-FOXO1 co-operate to make rhabdomyosarcomas more aggressive. Unfortunately the PAX3-FOXO1 and MYCN proteins are not easy to get at in cells. This inaccessibility means they are not what scientists are looking for as promising targets for new therapeutic approaches.
However, other genes are also involved in supporting roles for PAX3-FOXO1 and MYCN genes. Dr Shipley reasoned it might be worth tackling them as they seem to play a part in creating the aggressive behavior of rhabdomyosarcoma.
The project’s aim was to identify the genes that help promote aggression of the PAX3-FOXO1 and MYCN genes. The team termed these genes in supporting roles "effector" genes. Dr Shipley assessed those she could find and proposed, if appropriate, to make them the subject of subsequent studies. She would be determining their potential as new molecular therapeutic targets with the hope they would lead to new treatments.
The results of this successful study are currently being prepared for publication. One of the genes identified is already under intensive investigation in order to develop a therapeutic approach against it (in collaboration with the Centre for Cancer Therapeutics at The Cancer Research Institute).
- Walters, Z. S. et al. (2014) JARID2 is a direct target of the PAX3-FOXO1 fusion protein and inhibits myogeneic differentiation of rhabdomyosarcoma cells. Oncogene, 33(9). Read more: https://www.ncbi.nlm.nih.gov/pubmed/23435416
Presentations & Workshops
- Significance of the fusion genes in rhabdomyosarcomas. Presentation given at the Swiss Institute Bioinformatics. January, 2014. Lussanne, Switzerland.
- Significance of the fusion genes in rhabdomyosarcomas. Presentation given at the Geneva Hospital, Paediatric Department. January, 2014. Geneva, Switzerland.
- Rhabdomysarcoma: Critical Review of Research and Implications for Developing Therapies. Histone methylation status and differentiation therapy. Presentation given at Cold Spring Harbor Laboratory. May, 2014. New York, USA.
- Molecular Markers for Risk Stratification of Rhabdomyosarcomas. Presentation given at the Paediatric Soft Tissue Sarcoma Symposium and International Think Tank at the Pablove Foundation. November, 2014. Los Angeles, USA.
- Trends and challenges in (rare) cancer research? Presentation given at the Sarcoma Patients EuroNet 6th Scottish Personal Employers Network (SPAEN) Annual Conference. November, 2015. Paris, France.
- Challenges in lab-based sarcoma research. Presentation given at Sarcoma UK’s Research Symposium at The Royal Society of Chemistry. September, 2016. London, UK.
- Histone Modifications in Paediatric Sarcoma: Implications and Possibilities. Presentation given at the American Association of Cancer Research (AACR) Annual Meeting, Educational Session on Chromatin Regulation in Paediatric Cancer. April, 2017. Washington, USA.