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.

摘要