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).
- Z S Walters and J Shipley et al. ‘JARID2 is a direct target of the PAX3-FOXO1 fusion protein and inhibits myogenic differentiation of rhabdomyosarcoma cells’, Oncogene. 2013. 1–10.
- ‘Significance of the fusion genes in rhabdomyosarcomas’. Jan 2014. Swiss Institute Bioinformatics, Laussanne, and Geneva Hospital, Paediatric Department.
- ‘Histone methylation status and differentiation therapy’. Rhabdomysarcoma: Critical Review of Research and Implications for Developing Therapies. May 2014. Cold Spring Harbor U.S.
- ‘Molecular Markers for Risk Stratification of Rhabdomyosarcomas’. Pablove Foundation, Pediatric Soft Tissue Sarcoma Symposium and International Think Tank. Nov 2014. Children’s Hospital Los Angeles.
- ‘Trends and challenges in (rare) cancer research?’ SPAEN (Sarcoma Patient EuroNet) Nov 2015. Paris.
- ‘Challenges in lab-based sarcoma research’. Sarcoma UK’s Research Symposium. Sept 2016. The Royal Society of Chemistry, London.
- ‘Histone Modifications in Pediatric Sarcoma: Implications and Possibilities’. AACR (American Association of Cancer Research) Annual Meeting, Educational Session on Chromatin Regulation in Pediatric Cancer. April 2017. Washington DC.