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Novel Targets to Treat Head & Neck Cancer in Veterans

治疗头部的新目标

基本信息

批准号：
10512034
负责人：
UMAMAHESWAR DUVVURI
金额：
--
依托单位：
VETERANS HEALTH ADMINISTRATION
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-10-01 至 2025-09-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10512034
关键词：
11q13 Aerodigestive Tract Alcohols Animal Model Automobile Driving Bioinformatics Biological Assay Biological Markers Biological Process Biology Calcium Carcinogen exposure Carcinogens Carcinoma Caring Cell Culture Techniques Cell Survival Chloride Channels Chlorides Chromosomal Duplication Cisplatin Clinical Trials Cytotoxic agent Data Development Disease Dysplasia ERBB2 gene ERBB3 gene Enhancers Epidermal Growth Factor Receptor Epithelium Esophagus Event Excision Exposure to Family member Funding Gene Amplification Gene Expression Genes Genetic Genetic Transcription Genomics Goals Growth Head Head Cancer Head and Neck Cancer Head and neck structure Histologic Human In Vitro Investigation Investments Ion Channel Knockout Mice Larynx Lesion Leukoplakia MAP Kinase Gene MAPK Signaling Pathway Pathway MAPK3 gene Malignant - descriptor Malignant Neoplasms Malignant neoplasm of esophagus Malignant neoplasm of lung Mediating Methods Modeling Molecular Mus Neck Cancer Oncogenic Operative Surgical Procedures Oral cavity Outcome Oxidative Stress Oxides Pathway interactions Patients Physiological Play Precancerous Conditions Process Prognosis Proliferating Proto-Oncogene Proteins c-akt Reactive Oxygen Species Resistance Resources Role Runaway Sampling Services Signal Pathway Signal Transduction Specimen Squamous cell carcinoma Testing Therapeutic Tissues Tobacco Transcriptional Regulation Translating Tumor Promotion Up-Regulation Upper aerodigestive tract cancer Veterans Work aggressive therapy biological adaptation to stress cancer cell cancer diagnosis cancer invasiveness cancer therapy carcinogenesis carcinogenicity cell growth cell transformation experimental study genetic manipulation human tissue improved inhibitor insight keratinocyte malignant mouth neoplasm mouse model neoplastic neoplastic cell new therapeutic target novel oral tissue pharmacologic premalignant prevent progression risk promoter therapeutic target tobacco exposure transcription factor tumor tumorigenesis

项目摘要

Abstract Veterans suffer at a disproportional rate from squamous cell carcinoma of the upper aerodigestive tract, (SCCUADT) due to carcinogen exposure from tobacco and alcohol. Squamous cell carcinoma of the head (SCCHN), specifically the oral cavity and larynx is also driven by carcinogen exposure and comprises a lethal subset of these tumors. Despite aggressive treatments, SCCHN is a devastating disease that portends an overall 5-year survival of only ~50%. This Merit Review recently identified that an understudied ion channel, TMEM16A plays a key role in promoting SCCHN proliferation, by activating mitogenic signaling pathways. Not surprisingly, we found that TMEM16A interacts with EGFR family members, HER2 (Erbb2) and HER3 (Erbb3) and potentiates intracellular signaling. Interestingly, we surreptitiously discovered TMEM16A overexpression in pre-cancerous (dysplastic) tissues obtained from patients undergoing cancer treatment. This renewal application seeks to exploit this finding and determine if TMEM16A plays a critical role in cancer development, in addition to the role it plays in promoting the growth and proliferation of frankly malignant cells. This proposal therefore seeks to better understand the mechanism(s) by which SCCUADT develops, so that we may develop effective strategies to treat the pre-malignant condition before the development of invasive carcinoma. In order to reach this ultimate goal, we begin by proposing experiments that will elucidate the fundamental biologic process that underlie the formation of pre-malignant lesions, in the context of carcinogen exposure and define the mechanisms by which these lesions progress into invasive cancer. Aim I tests the hypothesis that TMEM16A overexpression is an early event that promotes carcinogenesis. We will (A) determine if TMEM16A is overexpressed in the earliest stages of carcinogenesis and (B) identify the molecular mechanisms that regulate this overexpression. We will accomplish this using both human tissues and a mouse model of carcinogen-induced SCCUADT. Firstly, we will determine if TMEM16A is overexpressed in tissues that have been exposed to carcinogen, even in the absence of histologic changes. We will also determine if the level of TMEM16A expression in premalignancy characterizes an increased risk of progression to invasive cancer. Second, we will extend these investigations to dissect the molecular mechanism(s) that regulate TMEM16A gene expression. Specifically, we will determine if gene amplification plays a role in this disease process. We also employ cutting-edge promoter occupancy assays to determine which transcription factors drive TMEM16A expression. Aim II tests the model that carcinogenesis is initiated by increased levels of oxidative stress (reactive oxygen species, ROS) which ultimately triggers a run-away cycle leading to increased TMEM16A and uncontrolled growth. In this Aim, we will (A) determine the signaling pathways that are activated by TMEM16A and (B) determine if TMEM16A inhibition will serve a therapeutic strategy to treat dysplasia. We postulate that increased ROS leads to upregulation of NRF2 signaling. NRF2 acts to increase TMEM16A transcription and ultimately promotes mitogenic signaling. Using a novel knock-out mouse model, we will determine if TMEM16A is required for carcinogenesis. Finally, we use pharmacologic inhibitors to target TMEM16A, and implicate it as a novel therapeutic target. At the end of the proposed funding cycle, we plan to have characterized the role of TMEM16A in the process of carcinogenesis of the UADT. We posit that this information will shed valuable insights into the biology of this understudied disease and identify novel targets that may ultimately prevent the development of cancer.

摘要