A new gene has been identified as a driver for treatment resistant Ewing sarcoma. Can this be a new target for treatment?
Despite intense multi-modality treatment the outcome for some patients with Ewing sarcoma (ES) remains poor. For those with metastatic disease at diagnosis only 1 in 5 survive to 5 years, with an even worse outcome for those who relapse. Furthermore, 30% of patients that have localised disease develop metastasis and rapidly succumb to their disease. These figures demonstrate the urgent need for improved biomarkers to identify patients at risk and new treatments to eradicate the cells responsible for relapse.
Ewing sarcoma is one of the most common cancers to affect bones or soft tissues. Long-term survival and quality of life for patients with drug resistant metastatic disease is poor. In part this is because current treatments do not eradicate the driver tumour cells that are responsible for drug resistance and recurrence, so called Ewing sarcoma cancer stem-like cells (ES-CSCs).
We funded Professor Susan Burchill at the University of Leeds to isolate and characterized ES-CSCs from tumours taken at diagnosis from patients with Ewing sarcoma. Using RNA sequencing the research team have identified some of the major drivers of drug resistance and self-renewal of these ES-CSCs and demonstrated that high expression of these drivers in tumours at diagnosis can identify those patients with the worst outcomes. Among other genes and proteins, they discovered that the NRXN1 gene and the protein it encodes, neurexin-1 were expressed at high levels in these cancer stem-like cells, and that their presence correlates to poor outcomes.
The team are already working with colleagues in Spain, Italy and Switzerland on a large study comparing neurexin-1 with other possible markers, to validate the best way to identify patients who would need treatment that is more intensive from the onset.
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