Targeting the Six1/Eya Transcriptional Complex to Inhibit Pediatric Sarcomas
Cancer and normal development share many properties. During development genes are activated to stimulate growth, migration, invasion and survival. These gene products are often lost once organ development is complete. In pediatric cancers, cells may arrest in a more progenitor/stem-like state, not fully differentiated and thus maintaining the expression of embryonic genes, which continue to promote embryonic processes. The Six1 gene encodes for a protein that induces the expression of genes that promote growth, survival, migration and invasion of cells during embryogenesis, and it is downregulated once development is complete. Six1 is highly expressed in numerous pediatric tumors, including Ewing sarcoma (EWS) and Rhabdomyosarcoma (RMS), and it is a key regulator of tumor spread (metastasis) in RMS. Interestingly, Six1 is unable to mediate these properties without another protein, called Eya, that helps Six1 activate the expression of other genes.
We recently demonstrated that Eya also plays a role in pediatric sarcomas, mediating survival/chemoresistance. We have previously demonstrated that Six1 requires a direct interaction with Eya to mediate tumor initiation and metastasis in adult cancers and will test if this is true in pediatric cancers. Because Six1 and Eya are expressed during development, lost in most developed tissues, but re-expressed in sarcomas, we hypothesize that the Six1/Eya complex is an ideal drug target whose inactivation will inhibit pediatric sarcoma growth and metastasis with limited side effects. This last point is critical, as the side effects associated with treatment of pediatric sarcomas are severe, and thus innovative, targeted therapies are sorely needed.
"The Alex's Lemonade Stand Foundation Innovation Award provides my group with our first opportunity to understand these pathways in pediatric sarcomas, and to attempt to target them to inhibit tumor progression. Without these funds, we would not have the resources to pursue these ideas, and thus this award is vital in allowing us to focus our efforts on identifying novel, less toxic means to inhibit pediatric cancers."