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: 10614397
• 负责人: Aaron Tward
• 金额: $ 53.04万
• 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/10614397
• 关键词: Address; Biological Markers; Biological Models; Biopsy; Biopsy Specimen; CDKN2A gene; Cancer cell line; Cancerous; Cell Reprogramming; Cell Separation; Classification; Clustered Regularly Interspaced Short Palindromic Repeats; Cold Therapy; Communities; Data; Disease; Dysplasia; Engineering; Event; Excision; FDA approved; 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; Modeling; Molecular; Monitor; Mutation; Natural History; Neoplasms; Oral; Oral cavity; Pathogenesis; Pathologic; Patients; Persons; Pharmaceutical Preparations; 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; neoplastic; next generation sequencing; novel; novel therapeutic intervention; novel therapeutics; oral dysplasia; patient subsets; pharmacologic; precision medicine; predictive marker; premalignant; response; standard of care; success; transcriptome sequencing; treatment strategy; tumor progression

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.

项目摘要： 口服潜在的肿瘤性疾病很常见，全球患病率约为4％， 仅在美国就有数百万个案件。这些港口的很大一部分组织病理学特征 口服发育不良，最有可能发展为口服鳞状细胞癌。尽管多年 对这些病变的研究，这些病变的管理方法是很大的。尤其， 因为我们缺乏这些病变的明确分子分类，所以我们没有良好的临床适用 预测哪些病变可能会发展为癌症的生物标志物（因此需要治疗）和 可能不会进展（因此可以观察到）。此外，我们对 负责将正常口服角质形成细胞重编程的突变的身份 角质形成细胞，然后是癌细胞。我们也不了解这些突变如何相互作用 为了引起发育不良，或如何利用这些知识来产生新颖的疗法 口腔发育不良的方法。本赠款中提出的工作旨在解决这些问题。首先，我们 将在大型口服异常面板上进行下一代测序，以定义突变 口腔发育不良的景观一般。接下来，我们建议对活检进行下一代测序 来自一组患者的纵向纵向遵循了口腔发育不良的几年的弧度 发展为癌症。接下来，我们利用原代人口腔中的新基因编辑系统 角质形成细胞与优化的有机模型系统相结合，以产生“设计师”口服异型症 病变并验证这些病变中的致病突变事件。最后，我们利用我们的优化 使用FDA批准的药物预测精确医学方法的有机模型系统。一次 完成，这项工作将作为口腔发育不良研究社区的基础数据资源，以及 将介绍小说，灵活且功能强大的模型系统，以解决口服质塑料中的关键问题 进展。