Tumor-specific PROTACs that exploit amplified MDM2 in dedifferentiated liposarcoma
The MDM2 oncogene is frequently amplified or overexpressed in sarcoma, particularly liposarcoma. Despite the development of selective MDM2 inhibitors, there are currently no effective clinical strategies to target tumors with amplified MDM2. This research proposal will test a new strategy using bifunctional protein degraders that redirect the E3 ligase activity of amplified MDM2 to tag essential proteins for degradation. The aims of this proposal are to: (1) Test the ability of these molecules to selectively kill highly MDM2-amplified liposarcoma cells while sparing normal cells that express physiologic levels of MDM2. (2) Test the durability of these molecules and define potential mechanisms/biomarkers of resistance. These studies will provide valuable data needed to fully understand the biology of MDM2 and develop effective and durable therapies to treat MDM2-amplified sarcomas such as liposarcoma.