Defining the mutational pathogenesis of oral preneoplasia

定义口腔癌前病变的突变发病机制

基本信息

批准号：
10217102
负责人：
Aaron Tward
金额：
$ 56.95万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
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/10217102
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

项目摘要

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。在口服异常时期，尽管多年来，病变最多才能发展为口服鳞状细胞癌对病变的研究，这些病变的管理方法尤其是可变的。因为我们缺乏病变的分类，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可能不会进步（因此可以进一步观察）。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，后来癌细胞。为了引起发育不良，或如何将这些知识纳入Genessel Therapel治疗对口服异常的方法将在大型口服异常板上进行下一个测序，以定义muter 一般而言，我们的口服异常景观。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下一个癌症。角质形成细胞与优化的器官模型系统相结合，生成“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。使用FDA批准的医学预测精确医学的器官模型系统。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，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步。