Osteosarcomas are a devastating pediatric bone cancer for which survival rates have not improved over 30 years. Current treatments remain aggressive and are prone to relapse. A new gene has been identified called Sox2, upon which osteosarcoma cells depend for survival. This project will evaluate whether strategies for blocking Sox2 function in tumors can eradicate the tumor and all residual cells to prevent relapse of the disease. These studies provide a novel basis for the targeted treatment of this childhood cancer and lead to a better understanding of the cancer stem cells that give rise to tumors.