Targeted Prevention for Non-Melanoma Skin Cancer

非黑色素瘤皮肤癌的针对性预防

• 批准号: 10252868
• 负责人: Clara Curiel-Lewandrowski
• 金额: $ 138.32万
• 依托单位: UNIVERSITY OF ARIZONA
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-10 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10252868
• 关键词: Actinic keratosis; Acute; Adjuvant; Age; Animal Model; Arizona; Basal cell carcinoma; Basic Science; Bioinformatics; Biological Markers; Carcinoma in Situ; Chemoprevention; Chemopreventive Agent; Clinical; Coupled; Dangerousness; Development; Drug Targeting; Epithelial; Experimental Models; Goals; Health; Health Care Costs; Histologic; Human; Incidence; Individual; Intraepithelial Neoplasia; Knowledge; Laboratories; Lesion; Light; Malignant Neoplasms; Medical; Modeling; Molecular Target; Morbidity - disease rate; Mus; Neoadjuvant Therapy; Neoplasms; Operative Surgical Procedures; Pathway Analysis; Pathway interactions; Pharmaceutical Preparations; Pharmacology; Phase I Clinical Trials; Preclinical Testing; Prevention; Prevention Research; Prevention approach; Prevention strategy; Preventive; Program Research Project Grants; Proteins; Proteomics; Recurrence; Research; Risk; Role; Safety; Signal Pathway; Signal Transduction; Skin; Skin Cancer; Skin Carcinogenesis; Skin Carcinoma; Squamous cell carcinoma; Systems Biology; TLR4 gene; Testing; Tissue Sample; Topical application; Translational Research; UV induced; Ultraviolet Rays; Universities; base; cancer therapy; clinical practice; cost; design; disorder risk; drug candidate; drug development; high risk; human subject; human tissue; in vivo; innovation; interest; molecular targeted therapies; mortality; mouse model; multidisciplinary; new technology; novel; novel therapeutics; phase 1 study; pre-clinical; precision medicine; preclinical study; premalignant; prevent; preventive intervention; programs; reflectance confocal microscopy; skin cancer prevention; skin damage; skin squamous cell carcinoma; small molecule inhibitor; sun damage; tertiary prevention; translational cancer research; translational research program

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.

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。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 使用最先进的蛋白质组阵列结合最新的探索性和 下游生物信息学方法和体内反射共聚焦显微镜非侵入性评估 以及人类皮肤组织样本的选择。这一高度集成的、基于翻译研究的计划 项目，强调多学科、精准医学方法预防皮肤鳞状细胞癌 也可作为预防其他上皮性恶性肿瘤的典范。