HOX Genes As Developmental Regulators Of Sarcomagenesis
This proposal combines the expertise of a pediatric cancer biologist and a developmental biologist, who is a world-renowned expert in the biology of musculoskeletal system development. Collaboration between these investigators creates a unique opportunity to advance our understanding of the developmental origins of Ewing sarcoma, an aggressive bone and soft tissue tumor that peaks in adolescence. Despite intensive therapy nearly a third of patients with Ewing sarcoma succumb to their disease and the quality of life of survivors is substantially reduced due to treatment-associated toxicities.
In addition, older adolescents have worse outcomes than children under ten, suggesting that there are fundamental differences in biology between "young" and "old" tumors that have yet to be elucidated. If outcomes for Ewing sarcoma are to improve, we need to better understand the biology of these tumors and develop novel approaches to therapy that are less toxic. In addition, if we can determine how tumors that arise in young children differ from those that present in teenagers, we can exploit this knowledge to improve therapies for the adolescent, young adult population.
In this proposal, we will use novel models to determine how disruption of a key developmental program called the Hox program leads stem cells in the developing bone to generate Ewing sarcomas. These studies will identify the earliest events in tumor initiation and determine how tumors are created at different life stages. Such insights will inform the development of novel, tumor-targeted therapies that can be devised to attack the root of the cancer.