Novel Targets to Treat Head & Neck Cancer in Veterans

治疗头部的新目标

• 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
• 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

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.

抽象的 退伍军人因上层机场消化道的鳞状细胞癌而遭受不利的速度， （SCCUADT）由于烟草和酒精暴露的致癌作用。鳞状细胞癌 （SCCHN），特别是口腔和喉头也由致癌物驱动，包括致命 这些肿瘤的子集。尽管有积极的治疗，SCCHN还是一种毁灭性疾病，预示 总体5年生存率仅为约50％。该优点评论最近确定了一个研究了一个研究的离子渠道， TMEM16A通过激活有丝分裂信号通路在促进SCCHN增殖中起关键作用。不是 令人惊讶的是，我们发现TMEM16A与EGFR家庭成员HER2（ERBB2）和HER3（ERBB3）互动 并增强细胞内信号传导。有趣的是，我们秘密地发现了TMEM16A的过表达 从接受癌症治疗的患者获得的癌前（发育不良）组织。这个更新 应用程序旨在利用这一发现并确定TMEM16A在癌症发展中是否起着关键作用， 除了它在促进坦率的恶性细胞的生长和增殖方面所起的作用。 因此，该建议试图更好地了解Sccuadt发展的机制 我们可能会制定有效的策略来治疗侵入性之前的恶性状况 癌。为了达到这个最终目标，我们首先提出的实验将阐明 在致癌物的背景下，基本的生物学过程是结构性病变形成的基础 暴露并定义这些病变发展为浸润性癌的机制。目标我测试 假设TMEM16A过表达是促进致癌作用的早期事件。我们将（a） 确定TMEM16A是否在癌变的最早阶段过表达，并且（b）确定分子 调节这种过表达的机制。我们将使用人体组织和小鼠来实现这一目标 致癌物诱导的SCCUADT的模型。首先，我们将确定TMEM16A是否在组织中过表达 即使没有组织学变化，也暴露于致癌物。我们还将确定是否 TMEM16A表达的水平在预示例中的表达表征了进展到侵入性的风险增加 癌症。其次，我们将扩展这些研究以剖析调节的分子机制 TMEM16A基因表达。具体而言，我们将确定基因扩增是否在该疾病中起作用 过程。我们还采用尖端的启动子占用分析来确定哪些转录因子 驱动TMEM16A表达。 AIM II测试了通过氧化应激水平升高（活性氧）引发致癌作用的模型 物种，ROS），最终触发了一个失控的周期，导致TMEM16A增加并不受控制 生长。在此目标中，我们将（a）确定由TMEM16A和（b）激活的信号传导途径 确定TMEM16A抑制是否会采用治疗发育不良的治疗策略。我们假设 ROS增加导致NRF2信号的上调。 NRF2的作用是增加TMEM16A转录和 最终促进有丝分裂信号。使用新型的敲除鼠标模型，我们将确定是否tmem16a 是癌变所必需的。最后，我们使用药理抑制剂来靶向TMEM16A，并将其牵连为 一种新颖的治疗靶标。 在拟议的资金周期结束时，我们计划表征TMEM16A在 UADT的致癌作用。我们认为，这些信息将使对此的生物学有宝贵的见解 正在研究的疾病并确定最终阻止癌症发展的新靶标。