Mechanisms of PAX3-FOXO1 and HES3 Cooperation in Rhabdomyosarcoma
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.