Advancing skin cancer prevention by tackling UV-induced clonogenic mutations

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Methods are available to prevent cutaneous squamous cell carcinoma (cSCC), the second most common cancer in the US, but are not appropriately used because currently established and mainstream prevention methods (sunscreen, photoprotective clothing) are often impractical and hard to use, and secondary prevention methods like field treatment with 5-fluorouracil cream, have numerous adverse effects. Therefore, less toxic and efficacious prevention methods are sorely needed. Several oral supplements are excellent candidates for primary and secondary prevention of cSCC. However, methods to evaluate their effectiveness in early photocarcinogenesis in a timely and financially feasible manner are lacking. Therefore, we lack data to drive their broader adaptation and predict their long-termefficacyfor human use. Ultraviolet light (UV) fromthe sun induces genomic damage, which is the primary cause of skin cancer. Early during carcinogenesis, UV radiation causes mutations in cells, resulting in the appearance of clusters of mutated cell clones, which later give rise to clinically apparent precancers and, ultimately, skin cancers. We call the mutations driving the growth of these cell groups clonogenic mutations (CMs). CMs are early changes during cSCC formation that appear decades before clinically detectable cancers. Based on previous evidence, CMs may indicate skin cancer risk and evaluate the efficacy of preventative treatment strategies and sun protection. CMs are present in low abundance in the skin, which makes them challenging to detect. However, recent advances in genomic sequencing technology and computational tools allow accurate identification and quantitation of CMs in the skin. We have shown that CMs can be accurately detected and used to evaluate sun-damaged skin areas and that CMs change during clinical secondary preventative therapy. The central hypothesis for this application is that CMs are biomarkers of sun- induced skin damage and that CMs can measure how well dietary supplements work as a preventative therapy. In the first set of studies, we will use Polypodium Leucotomos extract (PLE) and nicotinamide (NAM) as primary prevention agents to evaluate their effectiveness during UV exposure to reduce CMs and delay tumor initiation in a preclinical model. In the second set of studies, we will test NAM as a secondary prevention agent following UV exposure, which is known to induce cSCC. These studies will change how we evaluate a patient’s risk of developing skin cancer, determine the effect of early and easy-to-use skin cancer prevention, and provide crucial preliminary data for future clinical studies to establish the true efficacy of PLE, NAM, and other oral supplements on skin cancer risk reduction. These studies have the potential to shift the focus from treating skin cancer to preventing the occurrence of skin cancer, by improving prevention strategies and cancer care outcomes, and ultimately improving the lives of individuals with a history of sun damage and precancerous lesions. This work focuses on skin cancer; however, as CMs play a crucial first step in cancer growth in most human cancers the framework of this study will have implications for the broader field of cancer prevention.