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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：
10819716
负责人：
Aaron Tward
金额：
$ 21.79万
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/10819716
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

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.

项目总结:

项目成果

期刊论文数量（3）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

ORAOV1, CCND1, and MIR548K Are the Driver Oncogenes of the 11q13 Amplicon in Squamous Cell Carcinoma.

DOI：
10.1158/1541-7786.mcr-23-0746
发表时间：
2024-02-01
期刊：
Molecular cancer research : MCR
影响因子：
0
作者：
通讯作者：

A Hierarchy of Proliferative and Migratory Keratinocytes Maintains the Tympanic Membrane.

DOI：
10.1016/j.stem.2020.10.006
发表时间：
2021-02-04
期刊：
Cell stem cell
影响因子：
23.9
作者：
Frumm SM;Yu SK;Chang J;Artichoker JA;Scaria SM;Lee KP;Byrnes LE;Sneddon JB;Tward AD
通讯作者：
Tward AD

Epimorphic regeneration in the mammalian tympanic membrane.

DOI：
10.1038/s41536-023-00332-0
发表时间：
2023-10-18
期刊：
NPJ REGENERATIVE MEDICINE
影响因子：
7.2
作者：
Scaria, Sonia M.;Frumm, Stacey M.;Vikram, Ellee P.;Easow, Sarah A.;Sheth, Amar H.;Shamir, Eliah R.;Yu, Shengyang Kevin;Tward, Aaron D.
通讯作者：
Tward, Aaron D.