Ewing sarcoma is a rare cancer that mainly affects children and adolescents. Its onset and growth is driven primarily by EWS-FLI1, which belongs to a class of molecules called transcription factors that are integrally involved in gene regulation and are notoriously difficult to target for therapy. In Ewing sarcoma, EWS-FLI1 incorrectly switches certain genes “on” and “off,” giving rise to tumors in patients’ bones and the surrounding tissues. The current therapeutic approach comprises chemotherapy, radiation and surgery and—although this strategy is effective in many patients—it is less so in patients whose cancer has spread or relapsed. New therapies are desperately needed for this patient population.
To this end, the Grohar Laboratory’s research focuses on developing new therapies for pediatric sarcomas, in particular Ewing sarcoma. As a physician-scientist, Dr. Grohar employs a bench to bedside and back again approach to therapeutic development and has a number of projects in various stages of preclinical and clinical development. He and his team use a number of different approaches to identify and improve novel therapies that target EWS-FLI1 including:
These approaches have been used to identify compounds that repress EWS-FLI1 activity. To date, the lab has focused primarily on the compounds mithramycin, trabectedin and a series of analogs of both compounds. Future work focuses on characterizing the mechanism of this suppression and developing pharmacodynamic markers of EWS-FLI1 activity for clinical applications. These studies will aid in the translation of new therapies for Ewing sarcoma.