Defining the mutational pathogenesis of oral preneoplasia

定义口腔癌前病变的突变发病机制

• 批准号: 10037424
• 负责人: Aaron Tward
• 金额: $ 57.64万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-15 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10037424
• 关键词: Address; Archives; Biological Markers; Biological Models; Biopsy; Biopsy Specimen; CDKN2A gene; Cancer cell line; Cancerous; Cells; Classification; Clustered Regularly Interspaced Short Palindromic Repeats; Cold Therapy; Communities; Data; Disease; Dysplasia; Engineering; Event; Excision; FDA approved; Foundations; Future; Genes; Grant; Growth; Head and Neck Cancer; Human; Hybrids; In Vitro; Individual; Knowledge; Lesion; Leukoplakia; Low-Level Laser Therapy; Maintenance; Malignant Epithelial Cell; Malignant Neoplasms; Mediator of activation protein; Modeling; Molecular; Monitor; Mutation; Natural History; Oral; Oral cavity; Pathogenesis; Pathologic; Patients; Pharmaceutical Preparations; Pharmacology; Phenotype; Phototherapy; Precision therapeutics; Prevalence; Protein Analysis; Recurrence; Research; Resolution; Retinoids; Signal Transduction; Squamous cell carcinoma; System; Testing; Therapeutic; Time; Tissues; Uncertainty; United States; Validation; Work; causal variant; clinical application; data resource; deep sequencing; driver mutation; flexibility; individual patient; individual response; keratinocyte; mouth squamous cell carcinoma; mutational status; next generation sequencing; novel; novel therapeutic intervention; novel therapeutics; oral dysplasia; patient subsets; precision medicine; predictive marker; premalignant; response; standard of care; success; transcriptome sequencing; treatment strategy

Project Summary: Oral potentially preneoplastic diseases are common with worldwide prevalence of approximately 4%, and millions of cases in the United States alone. A large subset of these harbor the histopathological features of oral dysplasia, the lesions most likely to progress to oral squamous cell carcinoma. Despite years of research on these lesions, the approach to management of these lesions is quite variable. In particular, because we lack a clear molecular classification of these lesions, we do not have good, clinically applicable biomarkers that predict which lesions are likely to progress to cancer (and therefore require treatment) and which are likely to not progress (and therefore can be observed). Further, we lack a full understanding of the identity of the mutations responsible for reprogramming cells from normal oral keratinocytes into dysplastic oral keratinocytes, and subsequently to carcinoma cells. We also do not understand how these mutations interact in order to give rise to dysplasia, or how this knowledge could be harnessed to generate novel therapeutic approaches to oral dysplasia. The work proposed within this grant aims to address these questions. First, we will perform next generation sequencing on a large panel of oral dysplasias in order to define the mutational landscape of oral dysplasias in general. Next, we propose performing next generation sequencing on biopsies from a group of patients followed longitudinally over the arc of years whose oral dysplasias ultimately progressed to cancer. We next take advantage of novel gene editing systems in primary human oral keratinocytes combined with optimized organotypic model systems to generate “designer” oral dysplastic lesions and validate the causative mutational events in these lesions. Finally, we leverage our optimized organotypic model systems to predict a precision medicine approach using FDA-approved medications. Once complete, this work will serve as the foundational data resource for the oral dysplasia research community, and will introduce novel, flexible, and powerful model systems to address key questions in oral preneoplastic progression.

项目概要： 口腔潜在的癌前病变是常见的，全球患病率约为4%， 仅在美国就有数百万例病例。其中很大一部分具有组织病理学特征 口腔发育不良，病变最有可能进展为口腔鳞状细胞癌。尽管经过多年的 尽管对这些病变的研究不多，但这些病变的治疗方法相当多变。特别是， 因为我们对这些病变缺乏明确的分子分类， 预测哪些病变可能进展为癌症（因此需要治疗）的生物标志物， 其可能不会进展（并且因此可以被观察到）。此外，我们缺乏对 负责将细胞从正常口腔角化细胞重编程为发育不良口腔角化细胞的突变的鉴定 角质形成细胞，并随后转化为癌细胞。我们也不明白这些突变是如何相互作用的 为了引起发育不良，或者如何利用这些知识来产生新的治疗方法， 口腔发育不良的治疗方法这项赠款中提出的工作旨在解决这些问题。一是 将对一大批口腔发育不良进行下一代测序，以确定突变的 口腔发育不良的总体情况。接下来，我们建议对活检组织进行下一代测序， 从一组患者纵向跟踪了几年，他们的口腔发育不良最终 发展成癌症我们接下来利用新型基因编辑系统在原发性人类口腔癌中的应用。 角质形成细胞与优化的器官型模型系统组合以产生"设计师"口腔发育不良 并验证这些病变中的致病突变事件。最后，我们利用优化的 器官型模型系统，以预测使用FDA批准的药物的精确医学方法。一旦 完成后，这项工作将作为口腔发育不良研究社区的基础数据资源， 将介绍新颖，灵活，功能强大的模型系统，以解决关键问题，在口腔癌前病变 进展