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).
Using functional assays we have isolated and characterized ES-CSCs from tumours taken at diagnosis from patients with Ewing sarcoma. Using RNA sequencing we have identified 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. The expression of the strongest predictor of poor outcome (driver 1) is more than 100-times greater in ES-CSCs compared to other Ewing sarcoma cells, consistent with the hypothesis that it is a good candidate for the development of new treatment. However, two different proteins can be produced by the driver 1 gene, depending on the type and function of the cells.
In this study we will establish which of the proteins is expressed in self-renewing drug-resistant migratory ES-CSCs and predicts outcome of patients with Ewing sarcoma. We will also confirm the reported low expression of these proteins in normal cells and tissues, to assess any potential risk of targeted treatment-induced toxicities. These studies will identify which of the driver 1 proteins are the most promising as biomarkers of risk and candidates for the development of new treatments.
Study outputs will provide essential information to guide future research to exploit driver 1 to eradicate the drug resistant self-renewing ES-CSCs responsible for progression and relapse, with the goal of improving outcomes and reducing treatment associated morbidity through a targeted therapeutic approach. To accelerate this into early phase clinical trials we will evaluate the efficacy of FDA approved small molecules and drugs from a systematic review of the literature with known safety and bioavailability profiles.