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06/05/2024

Vall d'Hebron identifies a new therapeutic target for an aggressive childhood cancer affecting the muscles

Laboratori de Sarcomes Infantils

Children's Sarcoma Laboratory, within the Childhood Cancer and Blood Disorders group at VHIR.

Laboratori de Sarcomes Infantils

Children's Sarcoma Laboratory, within the Childhood Cancer and Blood Disorders group at VHIR.

06/05/2024

The research team has shown that inhibiting the TRIB3 protein slows the growth of rhabdomyosarcoma and improves survival in animal models.

Rhabdomyosarcoma is a type of childhood cancer that can appear in different parts of the body and affects soft tissues, especially muscles. It accounts for 5% of all pediatric tumors and, although in recent years there have been significant advances in its treatment, the life expectancy of patients with aggressive tumors is still low. A study in animal models* led by the Children's Sarcoma Laboratory, within the Childhood Cancer and Blood Disorders group at Vall d'Hebron Research Institute (VHIR) has identified a new strategy that could improve the evolution of children and adolescents with this aggressive cancer. The study, published in the journal Experimental Hematology & Oncology, has been carried out in collaboration with the Protein Kinases in Cancer Research group at VHIR and the Pediatric Oncology and Hematology and Pediatric Surgery Departments at Vall d'Hebron University Hospital.

In the development of cancer, and especially in pediatric tumors such as rhabdomyosarcoma, the patient's genetics play an important role. There are certain genetic errors or mutations that promote the onset of the tumor or determine that it is more malignant. This is the case of patients with aggressive or high-risk rhabdomyosarcoma, who usually have a specific genetic alteration: an abnormal union of two genes that leads to the PAX3-FOXO1 or PAX7-FOXO1 fusion proteins. “These proteins have altered functions that are related to metastasis and resistance to conventional therapies", explains Dr. Josep Roma, head of the Sarcoma Laboratory in the Childhood Cancer and Blood Disorders group at VHIR.

In this work, the team has focused on studying the regulatory role of the TRIB3 protein, which, in previous studies, had already been associated with resistance to treatment in rhabdomyosarcoma. The results show that, in this type of tumor, there are higher levels of TRIB3, which enhances the activity of the PAX3-FOXO1 fusion protein and also the malignancy of the tumor. As Dr. Roma states, "understanding the molecular mechanisms associated with rhabdomyosarcoma helps us to find therapeutic targets and more effective treatments to improve the survival and quality of life of patients".

With the aim of finding new therapeutic strategies based on these proteins, the effects of inhibiting TRIB3 were analyzed. Studies in rhabdomyosarcoma cell lines showed that, if TRIB3 is blocked, the levels of PAX3-FOXO1 and other pathways involved in the proliferation, survival or invasion of tumor cells decrease.

These results were confirmed in animal model studies: TRIB3 blockade slows tumor growth and improves survival. Thus, it shows that TRIB3 could be an interesting therapeutic target for the most aggressive subtype of rhabdomyosarcoma. "TRIB3 opens up promising new avenues of study to find future targeted therapies for rhabdomyosarcoma that we can offer to children and adolescents with this disease", concludes Dr. Roma.

The work has been possible thanks to funding received from the Catalan Institute of Oncology (ICO), the Carlos III Health Institute, La Marató de 3Cat Foundation, the Bosch Foundation, Tot per tu Initiative, the Amics Joan Petit Foundation, the Inocente Foundation and Mi Compañero de Viaje.

 

*Institutional Declaration on the Use of Animals in Research

“Understanding the molecular mechanisms associated with rhabdomyosarcoma helps us to find therapeutic targets and more effective treatments ”, states Dr. Josep Roma.

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Josep Roma  Castanyer

Josep Roma Castanyer

Main researcher
Childhood Cancer and Blood Disorders
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Lucas Moreno Martín-Retortillo

Lucas Moreno Martín-Retortillo

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Ariadna Garcia Rodriguez

Ariadna Garcia Rodriguez

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Constantino Sábado Álvarez

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