Targeted Prevention for Non-Melanoma Skin Cancer

非黑色素瘤皮肤癌的针对性预防

• 批准号: 10410013
• 负责人: Clara Curiel-Lewandrowski
• 金额: $ 23.45万
• 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/10410013
• 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; Genomics; 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; Persons; 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; 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; solar ultraviolet radiation; sun damage; tertiary prevention; transcriptome; translational cancer research; translational research program

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.

抽象的 非黑色素瘤皮肤癌的整体针对性预防 皮肤癌是全世界最常见的恶性肿瘤。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）每年都会发生。 NMSC 的发病率持续上升， 对皮肤癌的发病率和医疗保健费用产生重大影响，每年造成 81 亿美元的损失 治疗。这些病变中的大多数代表角化细胞肿瘤。本次多方合作的总体目标 机构计划项目拨款（PPG）旨在采用新技术并开发新的有针对性的预防措施 根除皮肤上皮内瘤变的策略（例如光化性角化病、鳞状细胞癌） situ），从而显着降低 cSCC 的风险。为实现这一目标，我们将开展多层次的 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 信号通路在导致 cSCC 发展的皮肤癌发生中的重要性； 2) 评估TLR4和TOPK/PRPK激活以及先前建立的信号传导之间的关系 AK 和 cSCC 发展的相关途径； 3）确定和开发新的治疗预防措施 在 cSCC 小鼠模型中特异性“击中”这些分子靶点并有效调节其分子靶点的药物 信号通路； 4）在临床前药理学模型中测试最有前途的靶向药物；和 5) 通过试点和一期临床试验评估选定药物的目标参与度和安全性。 了解太阳紫外线 (UV) 辐射信号通路中的关键分子靶标以及 开发可以击中并有效调节这些目标的多种局部给药药物 最终将允许基于精准医学的方法预防鳞状细胞癌。虽然这两个基础科学 项目（项目 1 和 2）旨在识别和验证紫外线诱导的信号通路和调节剂 为了实现这些目标，临床项目（项目3）将承担将领先候选药物从 小鼠模型进入急性太阳模拟光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和全转录组分析以及 最新的探索性和下游生物信息学方法以及体内反射共聚焦显微镜 对人体皮肤组织样本的非侵入性评估和选择。这种高度集成和转化的 基于研究的计划项目，强调采用多学科、精准医学方法进行预防 皮肤鳞状细胞癌也可以作为预防其他上皮恶性肿瘤的模型。