Targeting YAP/HIPPO pathway in embryonal rhabdomyosarcoma

Eleanor Chen, MD, PhD,  University of Washington
Recipient of the: $50,000 Ashley Davis Memorial/Miles 2 Give Research Award

Embryonal rhabdomyosarcoma (ERMS) is a cancer of skeletal muscle and is one of the most common pediatric sarcomas. The major clinical challenge is to identify novel and effective therapy for treating patients with relapse and advanced disease. The YAP/HIPPO signaling pathway is abnormally dysregulated in a variety of human cancers and has been shown to play an essential role in cellular processes essential for tumor progression. We have recently shown that expression of YAP is upregulated in ERMS compared to normal fetal muscle.  However, the role of YAP/HIPPO pathway in tumorigenesis of ERMS has not been previously explored. Our initial findings showed that knocking down YAP in a human ERM cell reduced tumor cell proliferation and induced differentiation. Our central hypothesis is that YAP-mediated HIPPO pathway drives tumor progression by modulating the differentiation status of tumor cell subpopulations. The proposed study will characterize the cellular effects of YAP on ERMS in vitro and in vivo in the context of gain-of-function and loss-function studies, utilizing an established zebrafish transgenic ERMS model and human ERMS cell lines. We will then apply ChIP sequencing and RNA sequencing studies to identify top candidate genes regulated by the YAP/HIIP signaling pathway in ERMS. Finally, we will further validate the efficacy of inhibiting YAP function on tumor growth in established ERMS xenograft model by both chemical and genetic approaches.  Targeting the YAP/HIPPO pathway represents a novel therapy platform for ERMS patients with relapsed and treatment-refractory disease.