Li-Fraumeni Syndrome (LFS) is a hereditary cancer predisposition syndrome caused by germline TP53 mutations, leading to a lifetime cancer risk exceeding 90% in women and 80% in men, with early onset of diverse tumor types including sarcomas, breast cancer, brain tumors, and pediatric adrenocortical carcinoma. Currently, no therapeutic interventions exist to prevent tumor development in LFS patients; management relies solely on intensive surveillance and prophylactic surgeries. This ASPIRE award explores a precision prevention strategy using rezatapopt, a novel small molecule designed to restore wild-type conformation and function to mutant p53-Y220C protein. Previous studies demonstrated that rezatapopt effectively reactivates p53-Y220C in tumors, suppressing their growth and restoring target gene regulation, with promising early-phase clinical trial results in patients harboring somatic Y220C mutations. However, although there are LFS patients with germline p53-Y220C mutations, rezatapopt has not been tested in the context of cancer prevention.
Here the investigators will assess the tolerability of rezatapopt in homozygous and heterozygous TP53-Y220C mice, evaluate its capacity to suppress tumorigenesis, and characterize pharmacodynamic effects on endogenous mutant p53 signaling. If successful, this approach could transform clinical care for LFS by enabling pharmacologic cancer prevention, alleviating the psychological and physical burden of lifelong surveillance, and informing broader strategies for targeted prevention in other hereditary cancer syndromes.