Funded by Bone Cancer Research Trust, the Ewing’s Sarcoma Research Trust, Great Ormond Street Hospital Charity, CCLG and CCLG Special Named Funds; #PearlPower, the Kieran Maxwell Legacy, Rosie Rocks the World, and the David Vernon Fund
Lead investigator: Professor Clare Davies and Dr Susanne Gatz, University of Birmingham
Award: £249,936.14
Awarded April 2025
The challenge
Ewing sarcoma is driven by a genetic error called EWSR1-FLI1, which helps the cancer cells replicate quickly and grow out of control. However, it is notoriously difficult to target for treatment. Instead, the researchers want to target EWS-FLI1 indirectly, by focusing on a process known as the ‘replication stress response’.
When the cancer cells are forced to grow faster by EWSR1-FLI1, it can cause a lot of damage to the new cancer cells - this is called 'replication stress'. Therefore, the fast growth has to be kept in check by molecules, such as the PRMT5 protein, that manage the replication stress response. This ensures that the cancer cells survive their fast growth.
Replication stress, therefore, represents a key vulnerability and potential target for treatment as, if it remains unchecked, the Ewing sarcoma cells will not survive.
The project
Led by Professor Clare Davies and Dr Susanne Gatz at the University of Birmingham, this project will investigate the role of PRMT5, which is a known drug target for several other cancers, in the replication stress response. They aim to investigate the link between PRMT5 and EWSR1-FLI1, exploring how they might work together to help Ewing sarcoma cells survive, and how this effect could be blocked by drugs known as ‘inhibitors’ of PRMT5. The researchers will look for possible markers which could show which Ewing sarcoma patients these drugs could work for, and will compare the levels and activity of PRMT5 in Ewing sarcoma and other (healthy and breast cancer) tissues.
Furthermore, this research will also explore whether combining PRMT5 inhibitors with other drugs also known to target aspects of the replication stress response could lead to a more effective treatment response.
The impact
Since EWSR1-FLI1 is very difficult to target, establishing a link with the more easily targeted PRMT5 could represent an exciting potential avenue for treatment. Several pharmaceutical companies are already testing PRMT5 inhibitors in clinical trials for adult cancers, which would mean this treatment could be given to patients much sooner than an entirely new drug would be.
If successful, this research could represent a significant step towards translation in Ewing sarcoma, leading to a much deeper understanding of the cancer's underlying biology and addressing the crucial need for more targeted, more effective treatment options with fewer toxic side effects.