ABSTRACTOverall Targeted Prevention for Non-Melanoma Skin CancerSkin cancer is the most common malignancy worldwide. One out of three new cancers is a skin cancer.Approximately 5 million cases of non-melanoma skin cancer (NMSC) basal cell carcinoma (BCC) andcutaneous squamous cell carcinomas (cSCC) occur annually. Incidence rates for NMSC continue to risecreating a substantial impact on morbidity and health care costs that account for $8.1 billion/year for skin cancertreatment. The majority of these lesions represent keratinocytic neoplasms. The overall goal of this multi-institutional Program Project Grant (PPG) is to employ novel technologies and develop new targeted preventionstrategies to eradicate intraepithelial neoplasias in the skin (e.g. actinic keratosis squamous cell carcinoma insitu) and thereby to dramatically reduce the risk of cSCC. To achieve this goal we will conduct a multilevelprogram of rational drug development including: 1) to assess in experimental models and human studies thesignificance of TLR4 and TOPK/PRPK signaling pathways in skin carcinogenesis leading to cSCC development;2) to evaluate the relationship between TLR4 and TOPK/PRPK activation and previously established signalingpathways of relevance in AK and cSCC development; 3) to identify and develop novel therapeutic preventiveagents that specifically hit these molecular targets in cSCC mouse models and effectively modulate theirsignaling pathways; 4) to test the most promising target-specific agents in preclinical pharmacology models; and5) to assess target engagement and safety of selected agents through pilot and Phase 1 clinical trials.Knowledge of the key molecular targets in solar ultraviolet (UV) radiation signaling pathways and thedevelopment of multiple topically administered agents that can hit and effectively modulate these targetsultimately will allow for precision medicine based approaches in cSCC prevention. While the two basic scienceprojects (Projects 1 and 2) aim to identify and validate UV-induced signaling pathways and agents that modulatethese targets the clinical project (Project 3) will undertake the task of moving leading candidate drugs frommouse models into acute solar simulated light studies and Phase 1 clinical trials. Novel technologies includesignaling network analysis using state-of-the-art proteomic arrays coupled with the latest exploratory anddownstream bioinformatic approaches and in vivo reflectance confocal microscopy for non-invasive assessmentand selection of tissue samples in human skin. This highly integrated and translational research based programproject emphasizing a multidisciplinary precision medicine approach for the prevention of cSCC of the skin canalso serve as a model for preventing other epithelial malignancies.