RMS account for around 6% of all childhood cancers and are broadly divided into two main histological subgroups: alveolar and embryonal RMS. Around 70–80% of alveolar cases are associated with PAX3/FOXO1 or PAX7/FOXO1 gene fusions.
Our work has shown that fusion gene negative alveolar RMS are clinically and biologically more similar to embryonal cases than alveolar and patients with PAX3/FOXO1 positive tumours are associated with poorer outcome.
This has important implications for risk stratification that are being incorporated into the next clinical trial by the European paediatric Soft tissue sarcoma Study Group (EpSSG). In addition, we have identified a gene signature associated with poor prognosis in fusion gene negative RMS that will be prospectively validated.
To find new approaches to treat these high-risk sarcoma patients we are identifying and validating:
- Molecular therapeutic targets and agents that are prioritised from a novel computational analyses of molecular and experimental data (in collaboration with Professor Bissan Al-Lazikani). These are then being tested in our preclinical models.
- Epigenetic modifying enzymes that have effects on the differentiation status or DNA damage response of RMS cells. These include the histone demethylase KDM4 family that is linked to a drug discovery project (collaboration with Professor Julian Blagg) and the histone methyl transferase EZH2 which is part of the polycomb repressive complex 2 (in collaboration with Dr Zoe Walters). This research aims to discover novel strategies for differentiation therapy and ways to make sarcoma cells more sensitive to current treatments which damage DNA.
Our research investigations are extended to desmoplastic small round cell tumours, liposarcomas, Ewing sarcomas and through collaboration with Professor Chris Lord, synovial sarcomas.
We have close links with clinicians at the Royal Marsden NHS Foundation Trust (in the Children and Young People's Unit and the Sarcoma Unit), the National Cancer Research Institute (NCRI) Clinical Studies Young Onset Sarcoma Subgroup (YOSS) and the European paediatric Soft tissue sarcoma Study Group (EpSSG).
These partnerships facilitate our research and take forward research advances to potentially benefit patients.
Support for our sarcoma research has come from: