Researchers at Thomas Jefferson University's Sidney Kimmel Cancer Center are advancing the development of a novel precision therapy that could offer new hope for patients with p53-mutated cancers. The innovative approach utilizes a proteolysis-targeting chimera (PROTAC) designed to target and degrade MDM2 proteins.
Dr. Christine M. Eischen, Herbert A. Rosenthal Professor of Cancer Research and co-director of the Blood Cancer Center of Excellence, presented the groundbreaking research at the 7th International Li-Fraumeni Syndrome Association Symposium. The work focuses on developing an anti-MDM2 PROTAC that activates the p73 gene, potentially triggering cancer cell death in patients with p53 mutations.
Mechanism of Action
The therapeutic strategy operates through a distinct mechanism where MDM2 degradation induces cellular stress, subsequently activating p73 – a p53 family member that shares many transcriptional targets with p53. "If we hit MDM2 and cause its degradation with a proteolysis-targeting chimera, what results is cellular stress that can activate a p53 family member called p73," explained Dr. Eischen. This activation leads to the upregulation of genes that promote apoptosis, or programmed cell death.
Development Status and Future Direction
The research team is currently focused on optimizing the MDM2 PROTAC compound before proceeding to clinical trials. "Once we have a [PROTAC] that is more optimized, we could get into [recruiting patients] for a clinical trial," stated Dr. Eischen. The researchers hypothesize that this approach could significantly impact patient outcomes by effectively targeting and eliminating p53-mutant cancers, potentially extending survival rates.
Ongoing Research
Beyond the immediate goal of treatment optimization, the team is investigating additional mechanisms that may contribute to the targeted death of cancer cells with mutant or deleted p53. This comprehensive understanding could enhance the therapy's effectiveness and potentially broaden its applications in cancer treatment.
The development of this anti-MDM2 PROTAC represents a potentially significant advancement in precision oncology, offering a new modality for treating cancers with p53 mutations, which are notoriously difficult to target effectively.
