Plexin-Semaphorin: a new signaling axis in Sarcomas

Charles Keller III, MD,  Children's Cancer Therapy Development Institute
Recipient of the: Race to Cure Sarcoma Research Award

The Plexin-Semaphorin pathway is previously unexplored as a target in sarcomas but may play a central role in the progression of the soft tissue sarcoma, rhabdomyosarcoma. Rhabdomyosarcoma is the most common soft tissue sarcoma in childhood, and the alveolar subtype of this tumor is known to have the poorest prognosis. More than half of children have unresectable primary tumors or metastatic tumors at diagnosis, and survival for non-localized unresectable recurrent disease is only 8 percent. Therefore, development of novel therapeutic strategies is urgently needed to improve cure rates. Our laboratory has developed a novel mouse model of alveolar rhabdomyosarcoma by genetically recapitulating the human alveolar rhabdomyosarcoma. This mouse model strongly reflects the features of human cases in terms of preferred primary sites of occurrence and high incidence of metastasis. By comparison of mouse and human tumor samples, we found that a cell membrane protein called PlexinB2 is overexpressed in tumor tissues of both species. Our proposal aims to investigate how this membrane protein works during the progression of this disease, thereby leading to the future development of novel therapeutic strategies for this aggressive childhood cancer.