A potential therapy to delay the progression of some sarcomas and tumours of the rare disease neurofibromatosis has been found

Neurofibromatosis causes tumours to form on the nerves mainly in the skin all over the body, brain and head. They are initially benign. However, such tumours develop into malignant cancers of the peripheral nerves in 10% – 20% of patients. Currently, there is no method to detect which tumours are likely to take this highly aggressive course.

The new paper, published in Clinical Cancer Research, discovers the existence of a protein, endoglin, linked to malignant peripheral nerve tumours. Endoglin contributes to the formation of blood vessels that feed the tumour as it grows out of control, allowing metastasis to develop.

The research, which uses animal models and human tumours, reveals the presence of endoglin in tumour cells and endothelial cells – the cells that line the inside of blood vessels – as well as in the blood that supplies tissues. It also shows that endoglin is actively involved in tumour growth and spread.

The study has been led by the Head of the CNIO Microenvironment and Metastasis Group , Héctor Peinado. The first author is Teresa González-Muñoz.

Potential use of endoglin in liquid biopsy

For Peinado, endoglin could contribute, along with other biomarkers, to the early detection of when a neurofibroma may malign or metastasise. In his opinion, in addition to tissue biopsies, “it would make sense to explore the potential use of endoglin as a biomarker in liquid biopsy”.

The research has also studied a treatment option for these malignant nerve tissue tumours, a therapy with antibodies that neutralise the effect of endoglin.

The research found that antibodies against endoglin reduced tumour cell proliferation and vascularisation in animal models, hence reducing tumour growth and metastasis.

The antibodies slowed the action of endoglin in tumour cells and also in blood plasma. “We believe that this option is effective because it attacks the tumour along with its environment, the tumour microenvironment,” clarifies Peinado.

In combination with drugs that have already been approved

On the other hand, it is common for patients to develop resistance in antibody treatments (the treatment stops being effective after some time). To address this problem, the team combined antibody therapy with an additional drug, MEK protein inhibitors (MEK proteins help control cell multiplication and survival). In effect, this strategy boosted the action of the antibodies.

According to Héctor Peinado, the next step would be “for this antibody therapy to enter a clinical trial, used in combination with MEK inhibitors”.

The authors also believe that this research paves the way to study the use of endoglin as a treatment for other types of sarcomas (soft tissue tumours).

Image: Teresa González Muñoz, first author, seated second from the left, with Héctor Peinado, standing in the center, and the rest of the members of the CNIO Microenvironment and Metastasis Group. / Laura M Lombardia CNIO

Reference article: Teresa González-Muñoz, Angela Di Giannatale, Susana Garcia-Silva, Vanesa Santos, Sara Sanchez-Redondo, Claudia Savini, Osvaldo Graña-Castro, Carmen Blanco-Aparicio, Suzanne Fischer, Olivier De Wever, Edgar Creus-Bachiller, Sara Ortega-Bertran, David J. Pisapia, José L. Rodríguez-Peralto, Juana Fernández-Rodríguez, Cleofe Romagosa, Rita Alaggio, Maria Serena Benassi, Laura Pazzaglia, Katia Scotlandi, Nancy Ratner, Kaleb Yohay, Charles P. Theuer, Héctor Peinado; Endoglin, a novel biomarker and therapeutical target to prevent malignant peripheral nerve sheath tumor growth and metastasis. Clin Cancer Res 2023; https://doi.org/10.1158/1078-0432.CCR-22-2462