Identification of Novel Treatment Targets by Exploring the Interaction of Rhabdomyosarcoma-Associated Oncogenes with Cellular Context in a Mouse Model of Rhabdomyosarcoma

Rhabdomyosarcoma is the most common soft-tissue cancer in children and adolescents and a highly aggressive from of cancer. Rhabdomyosarcoma resembles developing muscle tissue, and it is likely to arise as a 'developmental mistake' from progenitor cells that belong to the family of skeletal muscle cells. However, the precise cell type(s) from which rhabdomyosarcoma originates remain unclear. We argue here that it is important to understand the interplay between cancer-associated genes and the cell environment in which they take effect in order to develop novel, much needed treatments. Therefore, we propose to study the cancer-initiating effects of genetic events associated with rhabdomyosarcoma in different subtypes of muscle and non-muscle cells. The advantage of our proposed experiments is that we will freshly isolate discrete subsets of cells from genetically altered mice with an increased baseline risk of developing cancer and then introduce additional genetic changes before injecting the cells into recipient animals in order to test which subsets of cells grow into rhabdomyosarcoma tumors. We will then perform genomic screening to identify cellular programs that are differentially regulated between the tumor cells and their normal counterparts, and can be modulated pharmacologically. Finally, the therapeutic effect of selected candidate compounds in rhabdomyosarcoma will be screened in cell lines and in tumors in mice. We expect that findings from this proposed work will clarify the network of events that underlies rhabdomyosarcoma development, and thereby inform new strategies to treat this cancer.