The presence of metastases is the leading cause of cancer-related death. Despite advances in targeted cancer therapies, blocking the formation of metastases is still an unmet therapeutic need. A study led by the Childhood Cancer and Blood Disorders group at Vall d'Hebron Research Institute (VHIR) and the biotech company BCN Peptides has demonstrated the efficacy of a new drug, the synthetic peptide RA08, to reduce the formation of metastases in childhood and breast cancer. The work, published in Cellular and Molecular Life Sciences, was carried out in collaboration with the Pediatric Oncology and Hematology, Pediatric Surgery and Pathological Anatomy Services of the Vall d'Hebron University Hospital and the Institute of Biomedicine of Seville (IBiS).

In previous studies of the group, it has been described that the presence of high levels of the target protein integrin alpha9 (ITGA9) is associated with a high risk of metastasis. In this work, the researchers have analyzed the biological mechanisms by which ITGA9 favors the cells of some types of tumors to leave the primary tumor and travel through the organism to form a metastasis in another organ. Specifically, the role of ITGA9 in tumor invasion was investigated in cells and mouse models of neuroblastoma and rhabdomyosarcoma, two of the most common childhood tumors.

The researchers have identified that ITGA9 plays a key role in the metastasis of these childhood cancers. Specifically, it binds to ADAM proteins and allows the tumoral cell to adhere to its environment. In addition, it plays a relevant role in cell survival, proliferation, migration and invasion, all of which are key factors for metastasis. Knowing these functions is important for developing new therapeutic strategies. "One of the added values of this study is that, in addition to describing a relevant biological mechanism for metastasis, it also tests the antimetastatic effect of a new pharmacological product that has given exceptional results in animal models* and that can have a high impact on the prevention of metastasis", says Dr. Josep Roma, principal investigator of the Childhood Cancer and Blood Disorders group at VHIR.

A new therapeutic strategy against metastasis

"In the framework of this collaborative work, the company BCN Peptides has designed and is developing a new peptide drug, called RA08, aimed at interfering with the binding between ITGA9 and ADAM proteins to block the invasion of metastatic cells to other organs. Based on the key role of ITGA9 in the occurrence of metastasis, we have evaluated the effect of inhibiting this protein using the peptide RA08", explains Dr. Berta Ponsati, C.E.O. of BCN Peptides. RA08 is patented under PCT/EP2020/083987.

For the first time, this work has demonstrated in preclinical models that pharmacological inhibition of ITGA9 with the peptide RA08 significantly reduces metastasis formation, improving survival in mouse models of rhabdomyosarcoma and neuroblastoma, as well as breast cancer. The three types of tumor share the common feature that, although they generally have a high survival rate, this is greatly reduced when patients develop metastases.

The researchers also emphasize that RA08 does not present toxicity, since it does not affect cell proliferation or cause toxicity in preclinical models. In a therapy for the prevention of metastasis, having few side effects is key to ensuring success.

"Based on the results obtained, ITGA9 inhibition could be a promising therapeutic strategy to prevent the establishment of metastases in different tumor types. If RA08 was administered with standard therapies, it could improve patient survival", conclude Dr. Josep Roma and Dr. Berta Ponsati.

At VHIR, this research project was initiated thanks to a grant from La Marató de TV3 dedicated to minority diseases in 2009, which was subsequently supported by ACCIÓ/FEDER (RIS3CAT) and Instituto de Salud Carlos III. At a non-institutional level it has also had the support of Fundació Albert Bosch, Mi compañero de viaje Association, the Abidal Foundation and Tot per tu Association.

*Institutional Declaration on the Use of Animals in Research