Chemoprevention of Basal Cell Carcinomas with Tazarotene

他扎罗汀对基底细胞癌的化学预防

• 批准号: 6948626
• 负责人: Ervin HAROLD Epstein
• 金额: $ 93.36万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-09-13 至 2009-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6948626
• 关键词: antineoplastics; basal cell carcinoma; biological signal transduction; chemoprevention; clinical research; flow cytometry; gene expression; gene mutation; genetically modified animals; human subject; immunocytochemistry; laboratory mouse; neoplasm /cancer chemotherapy; neoplasm /cancer pharmacology; nevus; polymerase chain reaction; retinoids; terminal nick end labeling; western blottings

DESCRIPTION (provided by applicant): Patients with the basal cell nevus syndrome (BCNS) develop dozens to hundreds of basal cell carcinomas (BCCs) yearly due to mutations in the PATCHED1 gene, whose normal function is to inhibit hedgehog signaling pathway activation. All BCCs, whether sporadic or in BCNS patients, have as their pivotal abnormality activation of the hedgehog signaling pathway, generally as a result of mutational inactivation of PTCH1. Ptcl +/- mice also develop BCCs after carcinogenic insults and hence provide a good animal model for preclinical testing of chemopreventive interventions. Of the several such interventions we have assessed during the past four years in Ptcl +/- mice, topical applications of the retinoid tazarotene (taz) have by far the greatest efficacy, causing an approximately 85% decrease in BCC tumor burden (fig), a decrease which if replicated in BCNS patients would have a major impact on their lives. We propose to build on these exceptional results by (i) investigating the mechanism of the anti-BCC efficacy of taz through a comprehensive, iterative set of in vitro and in vivo experiments utilizing cell lines and mouse strains that we have developed and (ii) conducting a clinical trial assessing the chemopreventive and therapeutic efficacy of topical taz in human BCNS patients. This joint UCSF-Columbia project will take advantage of the scientific strengths of our institutions, the knowledge and laboratory resources we have accumulated over the past years of study of this problem, and in particular the unique large cohort of BCNS patients that we have assembled over the past 17 years of interacting with these patients. REVISED: April 22, 2004 (See Revision Note)

描述（由申请人提供）：由于补丁1基因中的突变，其正常功能是抑制HEDGEHOG信号通路激活的基因的突变，因此每年的基础细胞颈氏综合征（BCN）每年会产生数十个基础细胞癌（BCC）。通常，所有BCC，无论是零星还是BCNS患者，它们都是刺猬信号通路的关键异常激活，通常是由于PTCH1突变失活的结果。 PTCL +/-小鼠在致癌后也会发展BCC，因此为化学预防干预措施的临床前测试提供了良好的动物模型。在过去四年中，我们在PTCL +/-小鼠中评估的几项此类干预措施中，类维生素性tazarotene（TAZ）的局部应用具有最大的功效，导致BCC肿瘤负担降低了约85％的效力（无花果），如果在BCNS患者中复制的话，则会对他们的生活产生重大影响。我们建议通过（i）通过（i）通过我们开发的细胞系和（ii）进行临床试验的临床试验来评估人类BCNS中的临床试验，并进行临床试验，并（ii）进行临床试验评估了临床试验，以研究TAZ的抗BCC功效的机制。这个联合UCSF哥伦比亚项目将利用我们机构的科学优势，过去几年来研究这个问题的知识和实验室资源，尤其是我们过去17年与这些患者互动的独特大量BCNS患者。 修订：2004年4月22日（请参阅修订说明）