Project Funding Details

LAY SUMMARY (250 WORDS)
Alveolar rhabdomyosarcoma (aRMS) is an aggressive cancer of skeletal muscle. Survival for children in high-risk groups is less than 30%, and this has not improved appreciably in over 30 years. aRMS is characterized by the DNA mutation PAX3-FOXO1, which acts in part by tricking cells into thinking they are building muscle. Although PAX3-FOXO1 is found only in aRMS and should be an ideal drug target, it is not druggable. Our long-term goal is to identify proteins and pathways downstream of PAX3-FOXO1 amenable to pharmacologic blockade.

Several years ago, we created a model of aRMS by defining a cocktail of genes needed to change normal muscle cells to cells that mimic aRMS. Using this model, we figured out that PAX3-FOXO1 switches on a protein called RASSF4, which in turn silences a pathway that ordinarily limits cell growth. This pathway is called "Hippo," because organisms (for example laboratory flies and mice) with defective Hippo signaling have too many cells and organs that are too large. The main protein in the Hippo pathway is called MST1.

We suspect that in aRMS, PAX3-FOXO1 switches on RASSF4 to shut down MST1, resulting in too much cell growth and ultimately cancer. In this project we propose to determine using human cell-based and mouse models whether MST1 loss is critical for aRMS formation and also determine whether proteins downstream of MST1 might be useful drug targets. This work will provide a new roadmap for Hippo/MST1 in aRMS, and support development of novel therapies for this childhood cancer.

LAY SUMMARY (250 WORDS)
Alveolar rhabdomyosarcoma (aRMS) is an aggressive cancer of skeletal muscle. Survival for children in high-risk groups is less than 30%, and this has not improved appreciably in over 30 years. aRMS is characterized by the DNA mutation PAX3-FOXO1, which acts in part by tricking cells into thinking they are building muscle. Although PAX3-FOXO1 is found only in aRMS and should be an ideal drug target, it is not druggable. Our long-term goal is to identify proteins and pathways downstream of PAX3-FOXO1 amenable to pharmacologic blockade.

Several years ago, we created a model of aRMS by defining a cocktail of genes needed to change normal muscle cells to cells that mimic aRMS. Using this model, we figured out that PAX3-FOXO1 switches on a protein called RASSF4, which in turn silences a pathway that ordinarily limits cell growth. This pathway is called "Hippo," because organisms (for example laboratory flies and mice) with defective Hippo signaling have too many cells and organs that are too large. The main protein in the Hippo pathway is called MST1.

We suspect that in aRMS, PAX3-FOXO1 switches on RASSF4 to shut down MST1, resulting in too much cell growth and ultimately cancer. In this project we propose to determine using human cell-based and mouse models whether MST1 loss is critical for aRMS formation and also determine whether proteins downstream of MST1 might be useful drug targets. This work will provide a new roadmap for Hippo/MST1 in aRMS, and support development of novel therapies for this childhood cancer.