Targeted Prevention for Non-Melanoma Skin Cancer

摘要 非黑色素瘤皮肤癌的全面靶向预防 皮肤癌是世界上最常见的恶性肿瘤。三分之一的新癌症是皮肤癌。 大约500万例非黑色素瘤皮肤癌（NMSC）-基底细胞癌（BCC）和 皮肤鳞状细胞癌（cSCC）每年发生一次。NMSC的发病率继续上升， 对皮肤癌的发病率和医疗保健费用产生了重大影响，每年约有81亿美元用于皮肤癌 治疗这些病变大多数代表角化细胞肿瘤。这一多元的总体目标-- 机构计划项目赠款（PPG）是采用新技术和开发新的有针对性的预防 根除皮肤中的上皮内瘤形成（例如光化性角化病、鳞状细胞癌）的策略， 原位），从而显著降低cSCC的风险。为了实现这一目标，我们将进行多层次的 合理药物开发计划，包括：1）在实验模型和人体研究中评估， TLR 4和TOPK/PRPK信号通路在导致cSCC发展的皮肤癌发生中的意义; 2)评估TLR 4和TOPK/PRPK激活与先前建立的信号传导之间的关系 在AK和cSCC发展的相关途径; 3）确定和开发新的治疗预防 在cSCC小鼠模型中特异性“击中”这些分子靶点并有效调节其 4）在临床前药理学模型中测试最有前途的靶向特异性药物;以及 5)通过初步和1期临床试验评估选定药物的靶向作用和安全性。 了解太阳紫外线辐射信号通路中的关键分子靶点， 开发多种局部给药的药物，可以击中并有效调节这些靶点 最终将允许基于精确医学的方法预防cSCC。虽然两个基本的科学 项目（项目1和2）的目的是确定和验证紫外线诱导的信号通路和代理，调节 为了实现这些目标，临床项目（项目3）将承担将主要候选药物从 小鼠模型用于急性太阳模拟光研究和1期临床试验。新技术包括 使用最先进的蛋白质组阵列结合最新的探索性和 用于非侵入性评估的下游生物信息学方法和体内反射共聚焦显微镜 和人体皮肤组织样本的选择。这个高度综合和转化研究为基础的计划 项目，强调多学科，精确的医学方法来预防皮肤cSCC， 也可作为预防其他上皮恶性肿瘤的模型。

ABSTRACT Overall Targeted Prevention for Non-Melanoma Skin Cancer Skin 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) and cutaneous squamous cell carcinomas (cSCC) occur annually. Incidence rates for NMSC continue to rise, creating a substantial impact on morbidity and health care costs that account for $8.1 billion/year for skin cancer treatment. 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 prevention strategies to eradicate intraepithelial neoplasias in the skin (e.g. actinic keratosis, squamous cell carcinoma in situ), and thereby, to dramatically reduce the risk of cSCC. To achieve this goal, we will conduct a multilevel program of rational drug development, including: 1) to assess, in experimental models and human studies, the significance 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 signaling pathways of relevance in AK and cSCC development; 3) to identify and develop novel therapeutic preventive agents that specifically “hit” these molecular targets in cSCC mouse models and effectively modulate their signaling pathways; 4) to test the most promising target-specific agents in preclinical pharmacology models; and 5) 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 the development of multiple topically administered agents that can hit and effectively modulate these targets ultimately will allow for precision medicine based approaches in cSCC prevention. While the two basic science projects (Projects 1 and 2) aim to identify and validate UV-induced signaling pathways and agents that modulate these targets, the clinical project (Project 3) will undertake the task of moving leading candidate drugs from mouse models into acute solar simulated light studies and Phase 1 clinical trials. Novel technologies include signaling network analysis using state-of-the-art proteomic arrays coupled with the latest exploratory and downstream bioinformatic approaches and in vivo reflectance confocal microscopy for non-invasive assessment and selection of tissue samples in human skin. This highly integrated and translational research based program project, emphasizing a multidisciplinary, precision medicine approach for the prevention of cSCC of the skin can also serve as a model for preventing other epithelial malignancies.