Cancer-Causing Gene and Treatment Target for Ultra-Rare Rhabdomyosarcoma Confirmed Via Multiple Models

Cancer-Causing Gene and Treatment Target for Ultra-Rare Rhabdomyosarcoma Confirmed Via Multiple Models 1024 764 Katie Brind'Amour, PhD, MS, CHES

An international team has validated a cancer-causing gene fusion — and therapeutic targets — for an unusual presentation of muscle cancer in infants.

In 2016, researchers first identified a novel gene mutation and fusion in rare cases of infants with rhabdomyosarcoma, a type of skeletal muscle-like cancer, normally only seen in school-age children and teenagers. Taking that work to the next level, collaborators from Nationwide Children’s Hospital, Children’s Hospital Los Angeles, Paris’ Institut Curie Research Center, University of Texas Southwestern Medical Center and other institutions have now confirmed that the fusion is indeed cancer-causing, and two separate animal models and patient samples suggest a possible opportunity for therapeutic intervention for these children: the ARF6 pathway.

The research, published in Cell Reports, reveals that the specific mutated fusion gene, VGLL2-NCOA2, is capable of causing muscle cancer in both transgenic zebrafish and mouse allograft models. Furthermore, the team found that tumors in these models and in human patients over-express a gene called ARF6 that encodes a protein that cooperates with the fusion oncogene to produce tumors that have characteristics of immature skeletal muscle. When activated or overexpressed, ARF6 causes more aggressive disease.


Genevieve Kendall, PhD

“There is still a lot of work to be done to validate this process for rhabdomyosarcoma, but finding ARF6 is exciting because this target is already being explored as a therapy in adult cancers such as uveal melanoma,” says Genevieve Kendall, PhD, principal investigator in the Center for Childhood Cancer in the Abigail Wexner Research Institute at Nationwide Children’s and senior author on the publication.

A small molecule drug is already under investigation in some of these adult cancers to inhibit ARF6 activation. In the team’s research, inhibition of ARF6 resulted in lack of tumor formation.

“We have the chance to repurpose findings from adult cancers to an ultra-rare cancer in infants, which is very appealing,” says Dr. Kendall, whose next step with the models will be to determine if ARF6 inhibition is as effective in established tumors as it is in preventing tumor formation. “It could offer these infants the opportunity for targeted treatments instead of systemic chemotherapy and surgery, which can result in lifelong adverse side effects.”

Dr. Kendall’s work is primarily funded by an R01 grant from the National Institutes of Health to explore the context and impact of the rhabdomyosarcoma oncogene — and its various domains — at different points in development, as well as the importance of ARF6 across tumorigenesis. Their work is also supported by an Alex’s Lemonade Stand Foundation “A” Award and a V Foundation for Cancer Research V Scholar Award.

“Our work highlights the importance of collaborative efforts between clinical sequencing and basic scientists to build new models for pediatric cancer and rare diseases,” says Dr. Kendall. “Multiple models are so important because they identify from an evolutionary perspective the most conserved mechanisms of generating cancer and identify robust therapeutic opportunities. Successful application across multiple systems means a greater likelihood that therapeutic targets will be effective in clinical trials.”

The intersection of results from transgenic zebrafish (which have the human cancer gene inserted), the mouse allograft model (which has the human gene transduced into the muscle cells and engrafted to the leg of the mouse), and human RNA sequencing data collectively support the oncogene’s functional importance and the potential opportunity to control ARF6 expression as a therapy.

Despite the recency of the discovery of ARF6’s role in the inhibition of rhabdomyosarcoma, the ongoing work regarding the gene in adult cancers bodes well for a more rapid transition to pediatric trials.

“There is still a lot to do,” says Dr. Kendall, “but we are very optimistic that our line of multi-model investigation will meaningfully impact therapies for these children.”


  1. Alaggio R, Zhang L, Sung YS, Huang SC, Chen CL, Bisogno G, Zin A, Agaram NP, LaQuaglia MP, Wexler LH, Antonescu CR. A molecular study of pediatric spindle and sclerosing rhabdomyosarcoma: Identification of novel and recurrent VGLL2-related fusions in infantile cases. Am J Surg Pathol. 2016 Feb;40(2):224-35.
  2. Watson S, LaVigne CA, Xu L, Surdez D, Cyrta J, Calderon D, Cannon MV, Kent MR, Silvius KM, Kucinski JP, Harrison EN, Murchison W, Rakheja D, Tirode F, Delattre O, Amatruda JF, Kendall GC. VGLL2-NCOA2 leverages developmental programs for pediatric sarcomagenesis. Cell Rep. 2023 Jan 31;42(1):112013.

Image and video credits: Nationwide Children’s

Header image shows zebrafish that are two days old that express a human cancer gene found in pediatric sarcoma (magenta) in their developing skeletal muscle (cyan). Transgenic zebrafish are one of the cancer models used in Watson, LaVigne et al., to develop cross-species comparative oncology approaches for infantile rhabdomyosarcoma. They then implement these models to identify the most conserved drivers of the disease and therapeutic opportunities.

Courtesy of Genevieve Kendall, PhD

About the author

Katherine (Katie) Brind’Amour is a freelance medical and health science writer based in Pennsylvania. She has written about nearly every therapeutic area for patients, doctors and the general public. Dr. Brind’Amour specializes in health literacy and patient education. She completed her BS and MS degrees in Biology at Arizona State University and her PhD in Health Services Management and Policy at The Ohio State University. She is a Certified Health Education Specialist and is interested in health promotion via health programs and the communication of medical information.