Ewing sarcoma has a characteristic genetic mutation involving the fusion of two genes, EWSR1 and FLI1. This results in a cancer-driving ‘fusion protein’ (EWSR1-FLI1) which binds to DNA. However, whilst known to play a key role in the development of Ewing sarcoma, this protein is notoriously difficult to target for treatment.
Instead, a project led by Dr Sara Sánchez Molina, a sarcoma researcher based at the Institut de Recerca Sant Joan de Déu (IRSJD) in Barcelona, will use advanced techniques to indirectly target this key genetic fault. They will do so by investigating partners of the fusion protein that collaborate at the place in the DNA where it is binding and exerting its cancer-causing effects.
This approach harnesses ‘epigenetics’ which refers to the different ways in which our genetic code is influenced, without altering the code itself. For example, the way proteins may bind to the genetic code (DNA), causing the switching on or off of genes which can lead to cancerous change.
What are the aims of this research project?
Dr Sánchez Molina and team are aiming to develop a targeted approach to treating Ewing sarcoma by understanding what is happening at an epigenetic level.
Specifically, they will use state of the art technology to investigate how the EWSR1-FLI1 fusion protein and other proteins cluster together and support the reprogramming of cells from ‘normal’ to cancerous. The team will explore whether it is possible to bypass EWSR1-FLI1 and instead reverse this reprogramming by ‘untangling’ or disrupting these networks.
In doing so, they are hoping to identify a way of indirectly targeting EWSR1-FLI1 and preventing the processes leading to tumour development and progression, uncovering new approaches for treatment.
How could this project improve treatment options for Ewing sarcoma patients?
Treatment options for patients with Ewing sarcoma remain outdated, limited and extremely toxic. Whilst EWSR1-FLI1 is known to be the key genetic mutation driving tumour formation, treatment approaches directly targeting this crucial fusion protein remain challenging and have not yet reached clinic.
Building on developing evidence relating to the epigenetics of Ewing sarcoma, this research will explore the potential to harness a much needed alternative target and pave the way towards a kinder, more effective treatment.
This is one of four pioneering projects funded as part of a groundbreaking £800,000 joint investment into Ewing sarcoma research, made possible thanks to a collaboration between the Bone Cancer Research Trust, CCLG - The Children and Young People's Cancer Association, the Ewing's Sarcoma Research Trust and Great Ormond Street Hospital Charity.
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