Targeted Prevention for Non-Melanoma Skin Cancer

摘要 全面针对性地预防非黑色素瘤皮肤癌 皮肤癌是世界上最常见的恶性肿瘤。每三种新癌症中就有一种是皮肤癌。 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。NMSC的发病率继续上升， 对皮肤癌的发病率和医疗费用造成重大影响，每年皮肤癌的费用为81亿美元 治疗。这些病变中的大多数是角质形成细胞肿瘤。这一多项计划的总体目标是 机构方案项目赠款(PPG)是利用新技术和开发新的有针对性的预防措施 根除皮肤上皮内肿瘤的策略(例如光化性角化病、鳞状细胞癌 SITE)，从而极大地降低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 TLR4和TOPK/PRPK信号通路在皮肤癌发生发展中的意义 2)评估TLR4与TOPK/PRPK激活和先前建立的信号转导的关系 AK和CSCC发展中的相关途径；3)识别和开发新的治疗性预防措施 在CSCC小鼠模型中，特异性地“击中”这些分子靶点并有效地调节其 信号通路；4)在临床前药理学模型中测试最有希望的靶向特异性药物；以及 5)通过试点和第一阶段临床试验评估选定药物的靶向参与度和安全性。 太阳紫外线(UV)辐射信号通路中的关键分子靶点的知识 开发多种局部给药药物，以打击并有效调节这些靶点 最终将允许在CSCC预防中采用基于精确医学的方法。而这两门基础科学 项目(项目1和项目2)旨在识别和验证紫外线诱导的信号通路和调节剂 在这些目标中，临床项目(项目3)将承担将主要候选药物从 小鼠模型进入急性日光模拟研究和一期临床试验。新技术包括 利用最新蛋白质组阵列和全转录组分析结合的信号网络分析 最新探索性和下游生物信息学方法和体内反射共聚焦显微镜 人体皮肤组织样本的非侵入性评估和选择。这一高度集成和翻译的 以研究为基础的项目，强调多学科、精准医学的预防方法 皮肤鳞状细胞癌的研究也可作为预防其他上皮性恶性肿瘤的模型。

ABSTRACT Overall Targeted Prevention of 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 and whole transcriptome analysis 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.