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 退伍军人患上呼吸消化道鳞状细胞癌的比例不成比例， (SCUADT) 由于烟草和酒精中的致癌物质暴露。头部鳞状细胞癌 (SCCHN)，特别是口腔和喉部也受到致癌物暴露的影响，并包含致命的 这些肿瘤的子集。尽管进行了积极的治疗，SCCHN 仍然是一种毁灭性的疾病，预示着 总体 5 年生存率仅为约 50%。这篇优点评论最近发现了一个未被充分研究的离子通道， TMEM16A 通过激活有丝分裂信号通路，在促进 SCCHN 增殖中发挥关键作用。不是 令人惊讶的是，我们发现 TMEM16A 与 EGFR 家族成员 HER2 (Erbb2) 和 HER3 (Erbb3) 相互作用 并增强细胞内信号传导。有趣的是，我们秘密地发现TMEM16A在 从接受癌症治疗的患者身上获得的癌前（发育不良）组织。此次续订 应用程序试图利用这一发现并确定 TMEM16A 是否在癌症发展中发挥关键作用， 除了它在促进恶性细胞的生长和增殖方面发挥的作用之外。 因此，本提案旨在更好地理解 SCUADT 的开发机制，以便 我们可以制定有效的策略，在侵袭性发展之前治疗癌前病变。 癌。为了实现这一最终目标，我们首先提出实验来阐明 在致癌物质的背景下，形成癌前病变的基本生物过程 暴露并定义这些病变进展为浸润性癌症的机制。我的目标是测试 假设 TMEM16A 过度表达是促进癌发生的早期事件。我们将（一） 确定 TMEM16A 在癌发生的最早阶段是否过度表达，以及 (B) 鉴定分子 调节这种过度表达的机制。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 SCUADT 模型。首先，我们将确定TMEM16A在组织中是否过度表达 即使没有组织学变化，也已暴露于致癌物质。我们还将确定是否 癌前病变中 TMEM16A 表达水平的特征是进展为侵袭性风险增加 癌症。其次，我们将扩展这些研究来剖析调节的分子机制 TMEM16A 基因表达。具体来说，我们将确定基因扩增是否在这种疾病中发挥作用 过程。我们还采用尖端的启动子占据分析来确定哪些转录因子 驱动TMEM16A表达。 Aim II 测试了氧化应激（活性氧）水平增加引发致癌作用的模型 物种，ROS），最终触发失控循环，导致 TMEM16A 增加和失控 生长。在此目标中，我们将 (A) 确定由 TMEM16A 激活的信号通路和 (B) 确定 TMEM16A 抑制是否可以作为治疗发育不良的治疗策略。我们假设 ROS 增加导致 NRF2 信号传导上调。 NRF2 可以增加 TMEM16A 转录并 最终促进有丝分裂信号传导。使用新型敲除小鼠模型，我们将确定 TMEM16A 是否 是致癌作用所必需的。最后，我们使用药物抑制剂来靶向 TMEM16A，并将其暗示为 一个新的治疗靶点。 在拟议的资助周期结束时，我们计划描述 TMEM16A 在这一过程中的作用 UADT 的致癌作用。我们认为这些信息将为了解该疾病的生物学提供有价值的见解 对疾病进行充分研究并确定可能最终预防癌症发展的新靶标。