A research team at the Seville Biomedical Institute (IBis) has identified a new molecular mechanism that explains the high sensitivity of Ewing sarcoma (an aggressive bone cancer that mainly affects children and adolescents) to certain chemotherapy drugs, such as irinotecan. The results, published in the journal Oncogene, open the door to more personalised and effective strategies for treating this type of cancer.

The study was headed by Professors Enrique de Álava and Fernando Gómez-Herreros, whose groups worked closely together in the IBiS. Both of them co-supervised the doctoral thesis of José Joaquín Olmedo-Pelayo, first author of the work, which also involved leading national and international institutions.

A molecular Achilles’ heel
Ewing sarcoma is characterised by a very specific genetic alteration: the fusion of the EWSR1 and FLI1 genes. This produces an oncogenic chimeric protein known as EWS::FLI1. The fusion not only initiates and sustains tumour growth but also disrupts essential cellular processes. In this study, the researchers discovered that EWS::FLI1 sequesters a key protein, DHX9, impeding its natural function in resolving certain DNA/RNA structures known as R-loops. This results in an accumulation of these structures in the tumour cells, leading to genomic instability, replication stress and cell death, particularly after treatment with irinotecan, a topoisomerase I inhibitor that induces high R-loop levels in the cell.

‘We have identified a specific vulnerability in Ewing sarcoma that can be exploited therapeutically. This alteration in the R-loop resolution machinery not only explains sensitivity to irinotecan but also suggests new therapeutic combinations with ATR inhibitors that could enhance treatment efficacy,’ explains Fernando Gómez-Herreros, IBiS researcher and senior co-author of the study.

Clinical applications
Besides the biological value of the discovery, the findings have direct clinical potential. Firstly, the researchers observed that high levels of DHX9 are associated with a poorer prognosis, which suggests it could be used as a predictive biomarker for response. Secondly, blocking the interaction between EWS::FLI1 and DHX9 lowers accumulated genetic damage and provides resistance to irinotecan, reinforcing the functional relevance of the interaction.

‘The study helps us to understand why some patients with Ewing sarcoma respond particularly well to drugs such as irinitocan. But, above all, it provides us with clues to better stratify patients and design clinical trials with more rational, targeted combined therapies,’ says Enrique de Álava, head of the Pathology Department of the Virgen del Rocío University Hospital and the researcher heading the ‘Molecular pathology of sarcomas and other tumours’ group at the IbiS. ‘With a tumour as complex and aggressive as this, greater precision in treatment could make a real difference to survival rates.’

Collaboration and future prospects
The study is an example of successful multidisciplinary and inter-institutional collaboration. Taking part in the study, alongside Álava’s and Gómez-Herreros’s groups in Seville, were researchers from CIBERONC, the Carlos III Health Institute, Sant Joan de Déu Hospital, the Valencian Institute of Oncology, the University of Valencia, the German Cancer Research Center (DKFZ), the Hopp Children’s Cancer Center in Heidelberg, the IRCCS Rizzoli Orthopaedic Institute in Bologna and the University of Heidelberg, among others.

This project was made possible thanks to the Carlos III Health Institute, the Ministry of Science, Innovation and Universities, the Spanish Association Against Cancer Scientific Foundation, the University of Seville, the Pablo Ugarte Association, the La Sonrisa de Ale Association, and the María García Estrada Foundation.