Efficacy of a drug demonstrated in preclinical models to halt rhabdomyosarcoma growth

Ten years ago, Cristina's family-a girl who passed away from rhabdomyosarcoma-decided to transform their grief into a fight for life. At that time, there were no researchers at Sant Joan de Déu focused on finding a treatment capable of halting this type of pediatric cancer. Driven by hope, her parents launched a fundraising campaign that raised €600,000, also supported by the Leo Messi Foundation, which contributed €200,000. Their first goal was to fund a young pharmacologist, Estela Prada, with a very clear mission: to find an effective therapeutic approach against rhabdomyosarcoma. Ten years later, Dr. Estela Prada-recognized in 2024 with the prestigious Odile Schweisguth Award from the Société Internationale d'Oncologie Pédiatrique (SIOP) for the best early-career pediatric oncology researcher-has taken a decisive step toward that goal. Her work has allowed, for the first time, the demonstration of the efficacy of a drug in animal and preclinical models of this childhood tumor.

The study, "PRKG1 hinders myogenic differentiation and predicts response to AKT inhibitor Ipatasertib in Rhabdomyosarcoma", published in Nature Communications, was co-led by the Institut de Recerca Sant Joan de Déu (IRSJD) and the Hospital del Mar Research Institute (HMRIB), in collaboration with IRB Barcelona and the biotech company Nostrum Biodiscovery.

Rhabdomyosarcoma, one of the major challenges in pediatric cancer

Rhabdomyosarcoma is a type of malignant tumor that develops from skeletal muscle cells and is the most common sarcoma in pediatric patients. Although it can appear anywhere in the body, it is often located in the face, neck, pelvis, or limbs. In pediatric populations, rhabdomyosarcoma can severely affect the function of organs and tissues near the tumor, cause pain, inflammation, or movement difficulties, and requires intensive treatment.

Despite significant advances in understanding the molecular biology of rhabdomyosarcoma (RMS), several therapeutic uncertainties remain that hinder improved prognosis, especially in high-risk or relapsed patients, who still represent 25-30% of cases despite current treatments, including chemotherapy, surgery, and radiotherapy.

One of the main challenges is that no common molecular mechanisms have yet been identified that would allow the development of effective targeted therapies for all RMS subtypes. The tumor cells are muscle precursors that remain blocked in their maturation process, and it is still not fully understood what maintains this block or how it can be safely reversed.

Moreover, as often occurs in pediatric oncology, many available targeted drugs were initially developed for adults and have not been sufficiently evaluated in children, both due to biological differences and toxicity profiles, which complicates their clinical translation.

Drug effective in preclinical studies

The research demonstrates the efficacy of a drug in preclinical models developed from samples of patients with rhabdomyosarcoma at Sant Joan de Déu Hospital (HSJD), showing promising results for advancing toward new targeted therapies.

"Our goal has always been to translate laboratory advances into real patient benefit. Demonstrating the efficacy of this drug in models developed from samples of our rhabdomyosarcoma patients gives us great hope to continue advancing toward more specific and less aggressive treatments," explains Dr. Estela Prada, researcher in the Sarcomas and Neuroblastoma group at IRSJD and first author of the study.

PRKG1: a key biomarker for pediatric rhabdomyosarcoma treatment

The study also concludes that the PRKG1 gene plays an essential role in blocking a key protein in rhabdomyosarcoma biology and may act as a biomarker to predict response to the drug, an AKT inhibitor currently being evaluated in clinical trials for different types of cancer.

The work combines cellular and animal models of rhabdomyosarcoma and demonstrates that tumors with higher levels of PRKG1 respond best to the treatment. This finding could allow the selection of pediatric patients who could benefit most from this drug and opens the door to new, more personalized therapeutic approaches.

"This is a step forward in understanding this type of pediatric cancer and in translating knowledge from the lab to the patient. We now know that PRKG1 is not only a key player in tumor biology but also a target that can help guide therapeutic decisions in the future," highlights Dr. Jaume Mora, Scientific Director of the Pediatric Cancer Center Barcelona at HSJD, head of the Sarcomas and Neuroblastoma Research Group at IRSJD, and senior co-author of the article. He recently received the IV Beca FERO Dr. Baselga, endowed with €300,000, to continue advancing in the identification of a treatment against rhabdomyosarcoma.

In this regard, Dr. Inmaculada Hernández-Muñoz, senior co-author and researcher at the Hospital del Mar Research Institute (HMRIB), notes: "This discovery suggests the need to establish a new classification criterion for these tumors based on their cellular differentiation, regardless of underlying genetic alterations, and reinforces the notion that tumors appearing at early ages and during adolescence result from defects in human body developmental processes."

Families driving scientific research

Cristina was seven years old when, in September 2013, she was diagnosed with rhabdomyosarcoma. "After ten months of treatment, and when we least expected it, the disease returned. We then discovered that for these relapsed tumors there was no treatment nor ongoing research. We searched the world, spoke with experts from hospitals in Italy, France, and the United States, but could not find a solution for our daughter," recalls Laura Abella, Cristina's mother. In less than fifteen days, Laura and Juan Manuel, Cristina's parents, legally created the association against rhabdomyosarcoma and began working.

This research has been made possible thanks to the drive and determination of Cristina's family. Their dedication and solidarity have raised over €600,000 to advance research on an effective treatment for rhabdomyosarcoma.

Thanks to this support, the first phase of the project has been completed: demonstrating in an animal model the efficacy of a promising drug. However, many challenges remain, including evaluating this same drug in a clinical trial to determine its real effectiveness in pediatric patients.

Scientific research is a long and complex journey, but with the commitment and tenacity of families like Cristina's, that journey becomes undoubtedly shorter and more hopeful.