Identification of molecular targets promoting differentiation and loss of self renewal in osteosarcoma

David Scadden, MD,  Massachusetts General Hospital
Recipient of the: $50,000 Pittsburgh Cure Sarcoma Research Award

Osteosarcoma is the most common primary bone cancer affecting children and adolescences worldwide. However, since the introduction of chemotherapy, the overall survival rate has been plateaued for more than 30 years, remaining an unmet medical need. Here, we explore the potential of differentiation therapy in osteosarcoma, which aims specifically to promote terminal differentiation and loss of self-renewal in cancer cells. By performing a high-throughput drug screening in a mouse osteosarcoma cell model, we identified chemical compounds that triggered differentiation and decreased proliferation of osteosarcoma. Differentiated tumor cells exhibited the characteristics of mature osteoblasts or osteocytes including limited cell growth, the re-activated expression of osteoblastic genes and mineralization. Remarkably, they became more sensitive to chemotherapy in vitro and less tumorigenic in vivo. Mechanistically, we found the molecular targets among top candidates were enriched in HDAC, c-Met, VEGFR and MEK. Future efforts will be made to the validation of the function of differentiation inducers in human osteosarcoma cells and patient-derived xenograft models and the identification of molecular targets and biological mechanisms underlying the differentiation process. Collectively, this study aims to discover novel small molecules and molecular targets that promote terminal differentiation and loss of self-renewal in osteosarcoma and indicates that the therapeutic targeting differentiation process may be developed into a clinically relevant approach for the treatment of osteosarcoma.