New Therapeutic Target for Ewing Sarcoma Identified

Correlation of EphA2 membrane receptor with the metastatic capacity of tumors in Ewing sarcoma.

A potential new therapeutic target for Ewing sarcoma has been identified by the sarcoma research group of the Bellvitge Biomedical Research Institute (IDIBELL), led by Dr. Òscar Martínez-Tirado.

Ewing sarcoma is the second most frequent bone cancer in children and adolescents, and a tumor known by its aggressiveness and tendency to metastasize. The research, published in International Journal of Cancer, has been funded almost entirely by the Alba Pérez Foundation, a non-profit organization dedicated to this disease.

Two Mutations Linked to Ewing Sarcoma Subtype With Poor Prognosis
Frequent mutations in two genes that often occur together in Ewing sarcoma (EWS) have been identified by an international collaboration.

‘Targeting EphA2 membrane receptor could be a potential new therapeutic target for Ewing sarcoma.’

For years, the main line of research of the Ewing sarcoma group focused on the caveolin 1 protein (CAV1), which has been associated to treatment resistance and metastasis, among other issues. However, the location of this protein in the cell makes its use as a therapeutic target virtually impossible. "That is why we were looking for a CAV1 cofactor with an equally relevant role but a more accessible location", explains Dr. Martínez-Tirado, "and the EphA2 membrane receptor, already described in previous studies, meets these requirements."

In their latest work, researchers not only demonstrate the connection between the EphA2 receptor and caveolin 1, but also establish a correlation between the phosphorylation of EphA2 and the aggressiveness of tumors in Ewing sarcoma. "In several in vitro and in vivo tests, we observed that this membrane receptor plays a key role in the migration of tumor cells."

Regarding in vivo studies, the research team used two different models. The artificial model of metastasis, more experimental, allows researchers to assess the ability of cells to adhere to the pulmonary epithelium in adverse conditions. On the other hand, the new orthotopic model developed by the same group a few months ago induces a spontaneous metastasis, much more similar to what can be observed in a clinical setting.

Ewing Sarcoma Tumor Growth Accelerated by Single Genetic Abnormality
Bone cancer Ewing sarcoma is driven by a genetic abnormality that operates through two distinct processes, activating genes that stimulate tumor growth and suppressing those that prevent cancer.

"In the lab, we have shown that the lack of EphA2 receptor significantly decreases the incidence and number of metastases", says Dr. Martínez-Tirado, "and thanks to our collaboration with Hospital Virgen del Rocío, we also saw that 90% of Ewing sarcoma patients express this receptor (mimicking caveolin 1), a fundamental fact when it comes to selecting EphA2 as a therapeutic target. At the same time, working with patient samples also allowed us to correlate EphA2 ligand-independent activity, associated with its phosphorylation, with lower survival. "

Thanks to the stable financial support of the Alba Pérez Foundation, IDIBELL researchers will keep on working on the development of treatments based on blocking the activity of this receptor. "Through drug nanoengineering techniques, we aim to develop a molecule with a double effect, capable of blocking EphA2 in tumor cells and delivering other targeted drugs at the same time", concludes the IDIBELL researcher.