Advancing skin cancer prevention by tackling UV-induced clonogenic mutations

预防皮肤鳞状细胞癌(CSCC)的方法是可用的，CSCC是第二常见的癌症 在美国，但没有得到适当的使用，因为目前已经建立和主流的预防方法 (防晒服、防光服)往往不切实际，难以使用，二级预防方法 就像现场用5-氟尿嘧啶乳膏治疗一样，有许多不良反应。因此，毒性较小， 迫切需要有效的预防方法。几种口服补充剂是很好的候选者 慢性鳞癌的一级预防和二级预防。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方法。因此，我们缺乏数据来推动他们的 更广泛的适应性，并预测它们对人类使用的长期有效性。来自太阳的紫外光(UV)引起 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，导致突变细胞克隆的出现，这些克隆后来在临床上引起 表面上是癌症前期，最终是皮肤癌。我们把驱动这些细胞群生长的突变称为 克隆突变(CMS)。CMS是CSCC形成过程中的早期变化，出现在几十年前 临床上可检测到的癌症。根据以前的证据，CMS可能会指示皮肤癌的风险，并评估 预防性治疗策略和防晒措施的有效性。CMS在皮肤中的丰度很低， 这使得它们很难被检测到。然而，基因组测序技术的最新进展和 计算工具可以准确地识别和定量皮肤中的CMS。我们已经证明了CMS 可以准确地检测并用于评估阳光损伤的皮肤区域和临床过程中CMS的变化 二级预防治疗。这种应用的中心假设是CMS是太阳的生物标记物。 CMS可以衡量膳食补充剂作为预防性治疗的效果。 在第一组研究中，我们将使用白花蛇舌草提取物(PLE)和烟酰胺(NAM)作为主要成分 评价紫外线照射期间预防药物减少CMS和延缓肿瘤发生的有效性 在临床前模型中。在第二组研究中，我们将测试NAM作为二级预防制剂 紫外线照射，这是已知的诱发CSCC。这些研究将改变我们评估患者的风险的方式 发展皮肤癌，确定早期和易用的皮肤癌预防效果，并提供至关重要的 为未来临床研究确定PLE、NAM和其他口服补充剂的真正疗效提供初步数据 关于降低皮肤癌风险。这些研究有可能将重点从治疗皮肤癌转移到 通过改进预防策略和癌症护理结果预防皮肤癌的发生；以及 最终改善有日光损伤和癌前病变病史的人的生活。这部作品 关注皮肤癌；然而，由于CMS在大多数人类癌症的癌症生长中起着关键的第一步作用， 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.