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：
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
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/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

项目摘要

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) 的发病率每年持续上升。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 亿美元的损失大多数这些病变代表角化细胞肿瘤。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。为了实现这一目标，我们将进行多层次的研究。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 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标特异性药物； 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多种可以击中并有效调节这些目标的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，而这两项基础科学。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这种高度集成和转化的方法对人体皮肤组织样本进行非侵入性评估和选择。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。