Targeted Prevention for Non-Melanoma Skin Cancer

非黑色素瘤皮肤癌的针对性预防

基本信息

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
项目类别：
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

项目摘要

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.

抽象的非黑色瘤皮肤癌的总体靶向预防皮肤癌是全球最常见的恶性肿瘤。三个新癌症中的一个是皮肤癌。大约500万例非黑色素瘤皮肤癌（NMSC） - 基本细胞癌（BCC）和皮肤鳞状细胞癌（CSCC）每年发生。 NMSC的事件率继续上升，对皮肤癌/年占81亿美元的发病率和医疗保健费用产生实质性影响治疗。这些病变中的大多数代表角质形成性肿瘤。这个多重目标的总体目标机构计划项目赠款（PPG）是为了员工新颖的技术并开发新的针对性预防皮肤上上皮内肿瘤的策略（例如，光化性角化病，鳞状细胞癌原位），从而大大降低CSCC的风险。为了实现这一目标，我们将进行多级理性药物开发计划，包括：1）在实验模型和人类研究中评估 TLR4和TOPK/PRPK信号通路在皮肤致癌作用中的重要性，导致CSCC发育； 2）评估TLR4与TOPK/PRPK激活与先前建立的信号之间的关系在AK和CSCC开发中相关的途径； 3）识别和开发新型疗法预防性在CSCC小鼠模型中专门“击中”这些分子靶标并有效调节其的代理信号通路； 4）在临床前药理学模型中测试最有希望的目标特异性药物；和 5）通过试点和1阶段临床试验评估选定代理的目标参与和安全性。了解太阳紫外线（UV）辐射信号通路和开发多个可以击中并有效调节这些目标的额外给药的代理最终，将允许在预防CSCC中采用基于精确的医学方法。而两位基础科学项目（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的代理这些目标，临床项目（项目3）将承担从领先候选药物中移动的任务小鼠模型进入急性太阳能模拟光研究和1期临床试验。新技术包括使用最新的蛋白质组学阵列以及最新的探索性和最新的探索性和下游生物信息学方法和体内反射率共焦显微镜用于非侵入性评估以及人类皮肤中组织样品的选择。这个高度集成和翻译的基于研究的计划项目，强调预防皮肤CSCC的多学科，精确的医学方法还可以作为防止其他上皮恶质的模型。