Advancing skin cancer prevention by tackling UV-induced clonogenic mutations

方法可用于预防皮肤鳞状细胞癌（cSCC），第二大常见癌症 在美国，但没有得到适当的使用，因为目前建立和主流的预防方法 （防晒霜，光防护服）往往是不切实际的，很难使用，和二级预防方法 如现场使用5-氟尿嘧啶霜治疗，有许多不良反应。因此，毒性较小， 迫切需要有效的预防方法。一些口服补充剂是很好的候选人， CSCC的一级和二级预防。然而，早期评估其有效性的方法 缺乏及时和经济上可行的光致癌作用。因此，我们缺乏数据来驱动他们的 更广泛的适应性，并预测它们对人类的长期效用。来自太阳的紫外线（UV） 基因组损伤，这是皮肤癌的主要原因。在癌症发生的早期，紫外线辐射会导致 细胞中的突变，导致出现突变细胞克隆簇，随后引起临床上的 明显的癌前病变最终导致皮肤癌我们把驱动这些细胞群生长的突变称为 克隆突变（CM）。CM是cSCC形成期间的早期变化，出现在几十年前 临床上可检测的癌症。根据以前的证据，CM可能表明皮肤癌的风险，并评估 预防性治疗策略和防晒的功效。CM在皮肤中以低丰度存在， 这使得它们很难被探测到然而，基因组测序技术的最新进展和 计算工具允许皮肤中CM的准确识别和定量。我们已经证明，CM 可以准确地检测并用于评估晒伤的皮肤区域， 二级预防性治疗。该应用的中心假设是CM是太阳的生物标志物， 此外，CMs还可以测量膳食补充剂作为预防性治疗的效果。 在第一组研究中，我们将使用水龙骨提取物（PLE）和烟酰胺（NAM）作为主要的 预防剂，以评估其在UV暴露期间减少CM和延迟肿瘤发生的有效性 在临床前模型中。在第二组研究中，我们将测试NAM作为二级预防剂， UV暴露，已知其可诱导cSCC。这些研究将改变我们如何评估患者的风险， 发展中的皮肤癌，确定早期和易于使用的皮肤癌预防的效果，并提供至关重要的 为未来的临床研究提供初步数据，以确定PLE，NAM和其他口服补充剂的真实功效 降低皮肤癌风险的研究。这些研究有可能将焦点从治疗皮肤癌转移到 通过改善预防策略和癌症护理结果，预防皮肤癌的发生， 最终改善有日光损伤和癌前病变史的个体的生活。这项工作 然而，由于CM在大多数人类癌症的癌症生长中起着关键的第一步， 这项研究的框架将对更广泛的癌症预防领域产生影响。

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.