Novel Targets to Treat Head & Neck Cancer in Veterans

摘要 退伍军人患有上呼吸道鳞状细胞癌的比例不成比例， (SCCUADT)是由于烟草和酒精致癌。头部鳞状细胞癌 (SCCHN)，特别是口腔和喉部，也是由致癌物暴露引起的，包括致命的 这些肿瘤的子集。尽管进行了积极的治疗，但SCCHN是一种毁灭性的疾病，预示着 总体5年生存率仅为50%左右。这份功绩评论最近发现了一种研究不足的离子通道， 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 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。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， 此外，它还在促进恶性细胞的生长和增殖方面发挥作用。 因此，这项建议旨在更好地理解SCCUADT的发展机制(S)，以便 在侵袭性疾病发展之前，我们可以制定有效的策略来治疗癌前状态。 癌症。为了达到这一最终目标，我们首先提出了一些实验，这些实验将阐明 在致癌物质的背景下，形成癌前病变的基本生物过程 并确定这些病变进展为浸润性癌症的机制。AIM I测试 假设TMEM16A过度表达是促进癌症发生的早期事件。我们将(A) 确定TMEM16A在癌变的最早阶段是否过度表达，以及(B)确定分子 调节这种过度表达的机制。我们将使用人体组织和老鼠来完成这一任务 致癌物诱导的SCCUADT模型。首先，我们将确定TMEM16A是否在组织中过度表达 即使在没有组织学变化的情况下，也暴露在致癌物质中。我们还将确定是否 TMEM16A在癌前病变中的表达水平表现为进展为侵袭性风险增加的特征 癌症。其次，我们将扩展这些研究，以剖析调控的分子机制(S) TMEM16A基因表达。具体地说，我们将确定基因放大是否在这种疾病中发挥作用。 进程。我们还使用尖端启动子占有率分析来确定哪些转录因子 驱动TMEM16A表达式。 AIM II测试致癌是由氧化应激(活性氧)水平增加引起的模型 物种，ROS)，最终触发失控循环，导致TMEM16A增加和失控 成长。为此，我们将(A)确定TMEM16A和(B)激活的信号通路。 确定抑制TMEM16A是否将成为治疗异型增生的治疗策略。我们假定 ROS的增加导致NRF2信号的上调。NRF2促进TMEM16A转录和 最终促进有丝分裂信号。使用一种新的基因敲除小鼠模型，我们将确定TMEM16A 是致癌所必需的。最后，我们使用药物抑制剂来靶向TMEM16A，并将其牵连为 一种新的治疗靶点。 在拟议的供资周期结束时，我们计划确定TMEM16A在以下进程中的作用 UADT的致癌作用。我们假定，这些信息将为研究这一现象的生物学提供有价值的见解。 研究不足的疾病，并确定可能最终防止癌症发展的新靶点。

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.