Kendall Lab

We found that HES3 is a novel oncogenic target of PAX3-FOXO1. My group will now focus on how HES3 and PAX3-FOXO1 cooperate to inhibit developmental programs, such as myogenesis, and the cellular transcriptional response required for transformation. In parallel, to advance timely therapeutics in RMS, we will use chemical and genetic strategies to test a subset of clinically tractable targets identified in the more aggressive HES3-high RMS patient signature.

We have implemented genetic strategies to restrict cell lineage specific expression of human fusion-oncogenes in zebrafish systems. This is an ongoing collaboration with Koichi Kawakami at the National Institute of Genetics in Mishima, Japan. Over five years I have visited his lab and collected a unique sarcoma shelf screening resource consisting of over 50 transgenic zebrafish lines. These transgenic lines are being implemented to restrict the expression of human fusion-oncogenes to specific cellular compartments across a spectrum of developmental timepoints. Our efforts now include performing sarcoma shelf-screens to identify cell lineages that are resistant or susceptible to sarcoma fusion-oncogene expression. Further, we will understand the biology of these fusion-oncogenes by defining the genomic and transcriptional features of their in vivo activity. Comparing shared and unique vulnerabilities across multiple fusion-oncogenes will be a key approach for the identification of potential targets.

We are well positioned at Nationwide Children’s Hospital, and through multiple collaborations, to intersect with clinical sequencing efforts and validate novel oncogenic drivers. Our group generates new models of pediatric sarcoma by integrating newly identified fusion-oncogenes into the zebrafish genome to functionally validate their transformative capacity. These animal models allow us to understand the biology of these rare diseases in an appropriate developmental context and are a unique platform to identify potential targeted therapies.