Study unlocks potential new treatment strategy for aggressive childhood cancer

For many years pediatric rhabdomyosarcoma (RMS), the most common soft tissue cancer in children and teens, has had scientist scratching their heads in search of an effective treatment.

But a collaborative study from Aarhus University, University of Zurich and Stanford University, which was recently featured on the cover of Science Advances, provides novel insights that might render new avenues for development of drugs that could effectively target and stop the progression of the cancer.

With around 400 new cases in Europe and 400-500 in the US every year, RMS has a devastating prognosis for its aggressive form, alveolar RMS (aRMS). And its toxic chemotherapy treatments leave survivors with life-long side effects.

Using cutting-edge single-cell technologies, such as single-cell mass cytometry and single-cell RNA sequencing, the researchers were able to get a closer look and delve deep into the cellular and molecular complexity of the tumor.

The study found that aRMS tumors contained four main cell subpopulations, of which three were enriched in patients with worst outcomes, and one, which resembled differentiated muscle cells, was enriched in patients with better outcomes. By testing a library of drugs, researchers found that the abundance of the «more desired, less malignant » differentiated cells could be increased by targeting a signaling pathway called RAS. The good news is that drugs called RAS inhibitors are available in clinical settings, and have the potential to slow the growth of the cancer by targeting this pathway.

Could inform new treatment strategies

This discovery is a major step forward in the quest to find an effective treatment for aRMS – a cancer that is particularly challenging to treat due to its aggressive nature and resistance to traditional chemotherapy and radiation therapies.

“This study represents a significant advance in our understanding of RMS, as it provides insight into the molecular signatures and cell state transitions that underlie the aggressive behavior of the cancer. This knowledge has the potential to inform new treatment strategies that target the underlying biology of the disease, with the goal of improving outcomes for patients and reducing long-term side effects,” says Ermelinda Porpiglia, tenure-track Assistant Professor at the Department of Biomedicine at Aarhus University.

Cancer researchers are normally interested in identifying drugs that kill the malignant cells, such as chemotherapy. However, the discovery that some tumors contain “more favorable” subsets of cells and that tumor cells can be steered toward differentiation could be a game changer.

“This involves shifting focus from killing malignant cells to identifying a drug that shifts their composition into less-malignant differentiated cells”, says Sara Danielli, the lead author of the study, who dedicated her PhD research in Prof. Schäfer’s lab at the University of Zurich to tackle this question.

Further research is needed

According to Ermelinda Porpiglia these findings are of interest for the cancer and muscle biology field in general and patients with RMS in particular.

While the results of the study are promising, to find an effective treatment without debilitating side-effects requires further research.

“These findings, which uncover a susceptibility of human aRMS to RAS inhibitors, despite the absence of a mutation in the RAS pathway, suggest that targeting the RAS pathway may be a promising strategy for treating alveolar rhabdomyosarcoma. However, further research is needed to fully understand the potential of these inhibitors as therapeutic agents for this disease,” says Ermelinda Porpiglia.

Learn more about the study that is featured on the latest online cover of the scientific publication Science Advances here.

Behind the research results:

Study type:  Basic research study

Collaborators:  University of Zurich: Lead Author Sara Danielli, Professor Beat Schäfer, Senior Scientist Marco Wachtel; Stanford University: Professor Helen M. Blau

External funding:  Cancer League Switzerland KLS-5143-08-2020 to B.W.S., Swiss National Science Foundation 3100-175558 to B.W.S., Childhood Research Foundation Switzerland to B.W.S., Sarcoma Foundation of America grant to B.W.S., Children’s Research Center grant from the University Children’s Hospital Zurich 10788_E to S.G.D., California Institute for Regenerative Medicine grant RB5-07469 to H.M.B., Baxter Foundation to H.M.B., BD Biosciences Stem Cell grant to E.P.

Contact: 

Ermelinda Porpiglia, tenure-track Assistant Professor
Department of Biomedicine, Aarhus University
Mail: eporpiglia@biomed.au.dk