Chemo-prevention of UVB-induced Basal Cell Carcinomas

[unreadable] DESCRIPTION (provided by applicant): [unreadable] Solar UVB radiation is a well-known major risk factor for the induction and development of non-melanoma skin cancers (NMSCs), which include both basal cell carcinomas (BCCs) and squamous cell carcinomas (SCCs). The carcinogenic effects of environmental UVB exposure are thought to retard the direct induction of structural changes in DNA, such as cyclobutane pyrimidine dimers and 6-4 photoproducts, leading to mutations in the form of C to T and CC to TT transitions (UVB signature mutations). These mutations are present in the p53 gene of the majority of SCCs, BCCs, actinic keratoses and in non-tumor skin adjacent to these lesions. Skin BCCs are the most common form of human cancer, affecting at least 750,000 Americans each year. The molecular mechanism of BCCs induction involves activation of the sonic hedgehog (shh) pathway. Extensive experimental evidence confirms that cutaneous UVB exposure induces UVB signature mutations both in p53 and in ptch genes, which together likely play an important role in blocking apoptosis and augmenting proliferation and clonal expansion of initiated cells leading to BCCs induction of BCes. We propose that rescuing mutant p53 and blocking shh pathway activation together using a combinatorial approach in ptchheterozygous mice could provide additive and/or synergistic protection against BCCs. To test this hypothesis, we will employ a genetically engineered murine model of BCCs development and use combination of a rescuer of mutant p53 conformation and function, CP-31398 and a specific inhibitor of the shh pathway, cyclopamine. It is our belief that this animal model combined with the study of chemical agents capable of rescuing mutant p53 and inhibiting shh pathway activation provides a uniquely effective approach for testing innovative mechanism-based strategies for the chemoprevention of NMSCs. [unreadable] [unreadable]