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Mechanisms of PAX3-FOXO1 and HES3 Cooperation in Rhabdomyosarcoma

Nationwide Children’s Hospital
Genevieve Kendall, PhD
Grant Type: 
'A' Award Grants
Year Awarded: 
Type of Childhood Cancer: 
Project Description: 

Researcher Update (January 2023) 

Genevieve Kendall, PhD from Nationwide Children’s Hospital and The Ohio State University is a two-time ALSF grant recipient and one of the most recent pediatric cancer experts to join ALSF’s Scientific Advisory Board. Her research focuses on pediatric rhabdomyosarcoma, a cancer characterized by molecular features of impaired skeletal muscle development. Currently no curative treatments are clinically available, but Dr. Kendall aims to change that.

In 2015, Dr. Kendall received an ALSF Young Investigator award for her project, Zebrafish Modeling of PAX3-FOXO1 Driven Rhabdomyosarcoma. This helped her to fill a critical gap in rhabdomyosarcoma research — a lack of diverse animal models. She engineered zebrafish models with a human PAX3-FOXO1 gene fusion integrated into their DNA to learn more about how this mutation interacts with other genes and turns normal cells into cancerous cells. It is known that PAX3-FOXO1 is the key oncogenic driver of rhabdomyosarcoma, but questions about how it operates and how to best target PAX3-FOXO1 remain. Dr. Kendall’s team discovered that a gene known as HES3 is the direct target of PAX3-FOXO1.

In 2018, she received an ALSF ‘A’ Award to further investigate the Mechanisms of PAX3-FOXO1 and HES3 Cooperation in Rhabdomyosarcoma (more on that project below). Thanks to her innovative model system, we now know that HES3 works with PAX3-FOXO1 to interfere with muscle cell maturation in fusion positive rhabdomyosarcoma. Furthermore, her team was surprised to find that PAX3-FOXO1 also turns on a myriad of genes associated with a neural program. She continues to study the pathways and processes that PAX3-FOXO1 leverages at the early stages of tumorigenesis and during tumor evolution.

The ultimate goal of this research is to find new therapies that will improve the future for children with rhabdomyosarcoma. When looking at gene expression signatures in rhabdomyosarcoma patients, Dr. Kendall and collaborators found that the fibroblast growth factor receptor 4 (FGFR4) gene is highly coexpressed with HES3. This is particularly exciting as other research groups are in the preclinical stages of targeting FGFR4 in rhabdomyosarcoma as a therapeutic opportunity. We look forward to more promising discoveries from the Kendall Lab and to Dr. Kendall’s contributions as an ALSF Scientific Advisory Board member. You can read more about her work on The Childhood Cancer Blog


Rhabdomyosarcoma is the most common soft tissue sarcoma in children and has no targeted treatment options. The most aggressive forms of rhabdomyosarcoma are caused when pieces of two chromosomes break off and fuse together and create an abnormal protein called PAX3-FOXO1. This new protein turns on and off hundreds–if not thousands–of genes, transforming a normal cell into a cancer cell.  The exact mechanism of how PAX3-FOXO1 accomplishes this is unknown and insight into this process is hindered by the lack of models.

I developed zebrafish models of rhabdomyosarcoma that allow me to study PAX3-FOXO1 activity in the context of vertebrate development. I found that by inserting human PAX3-FOXO1 into the zebrafish genome that zebrafish develop rhabdomyosarcoma that is consistent with the human disease. By studying my new zebrafish model, I discovered that PAX3-FOXO1 turns on an important gene, HES3, which correlates to poor prognosis in patients.

I will probe the important pathways and processes by which PAX3-FOXO1 and HES3 cooperate in more aggressive rhabdomyosarcoma. This includes understanding how PAX3-FOXO1 and HES3 inhibit muscle cell maturation and how this functions in more aggressive disease. I have also identified targets downstream of PAX3-FOXO1 and HES3 for drugs that are currently in clinical trials for other cancers. I will investigate the efficacy of these drugs in pediatric rhabdomyosarcoma to repurpose them for timely use in the clinic. Using short- and long-term strategies, and diverse robust model systems, my goal is to identify novel therapies or therapy combinations for children battling rhabdomyosarcoma.

Co-funded by: 
Flashes of Hope
Tap Cancer Out