Tumor-specific PROTAC development as a new therapeutic approach for osteosarcoma

Dr. Gunda Georg, Ph.D. – Regents of the University of Minnesota - Twin Cities, Minneapolis, MN 

This proposal addresses a need for the development of a safe and new therapeutic approach for treating an aggressive cancer, osteosarcoma. Osteosarcoma is one of the most prevalent bone cancers in children and young adults, with a 30% 5-year survival rate when pulmonary metastases are detected. Current standard of care for localized osteosarcoma includes surgery and chemotherapy, which can achieve long-term survival in only 60% of cases. No new approaches have been developed since the 1980s. To address this gap in development, we are developing a new therapeutic strategy against two well-established targets in osteosarcoma, BRD4 and the WEE1 kinase. While inhibitors have been developed, a limitation to inhibiting these proteins is the significant dose-limiting toxicities that patients experience. To overcome these toxic side effects, we are developing first-in-class tissue-specific molecules capable of degrading either the BRD4 protein or the WEE1 kinase in tumor tissue while sparing healthy cells. Our team has significant expertise in therapeutic development for both proteins and has already developed preliminary data supporting our ability to degrade the BRD4 protein in osteosarcoma cells and downregulate the cancer oncogene c-MYC, which is dysregulated in almost 50% of all cancers. These findings can also be extended to treating additional adult and pediatric cancers, including neuroblastoma. We anticipate this new approach will be more efficacious than existing inhibitors.