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：
10681505
负责人：
Aaron Tward
金额：
$ 14.52万
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：
2022
资助国家：
美国
起止时间：
2022-09-01 至 2025-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10681505
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 Persons 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.

项目概要：口腔潜在肿瘤前期疾病很常见，全球患病率约为 4%，仅在美国就有数百万病例具有组织病理学特征。口腔异型增生的病变最有可能进展为口腔鳞状细胞癌。对这些病变的研究，这些病变的治疗方法变化很大，特别是。因为我们对这些病变缺乏明确的分子分类，所以我们没有良好的、临床适用的方法预测哪些病变可能发展为癌症（因此需要治疗）的生物标志物以及此外，我们对这一点缺乏充分的了解。负责将细胞从正常口腔角质形成细胞重编程为发育不良口腔的突变的身份我们也不了解这些突变如何相互作用。为了引起发育不良，或者如何利用这些知识来产生新的治疗方法这笔拨款中提出的工作旨在解决这些问题。将对大量口腔发育不良进行下一代测序，以确定突变接下来，我们建议对活检进行下一代测序。来自一组经过多年纵向随访的患者，这些患者最终出现了口腔发育不良接下来，我们在初级人类口腔中利用新型基因编辑系统。角质形成细胞与优化的器官模型系统相结合，产生“设计师”口腔发育不良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 批准的药物预测精准医疗方法的器官模型系统。完成后，这项工作将作为口腔发育不良研究界的基础数据资源，并且将引入新颖、灵活且强大的模型系统来解决口腔癌前病变的关键问题进展。