Novel Targets to Treat Head & Neck Cancer in Veterans

摘要 退伍军人患上呼吸消化道鳞状细胞癌的比例不成比例， （SCCUADT）由于烟草和酒精的致癌物暴露。头颈部鳞状细胞癌 （SCCHN），特别是口腔和喉也受到致癌物暴露的驱动，并包括致命的 这些肿瘤的一部分。尽管有积极的治疗，SCCHN是一种毁灭性的疾病，预示着一个 总体5年生存率仅约50%。这一优点审查最近确定，一个研究不足的离子通道， TMEM16 A通过激活促有丝分裂信号通路在促进SCCHN增殖中起关键作用。不 令人惊讶的是，我们发现TMEM 16 A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，我们偷偷地发现了TMEM16A的过度表达。 从接受癌症治疗的患者获得的癌前（发育异常）组织。此续订 本申请试图利用这一发现并确定TMEM16 A是否在癌症发展中起关键作用， 除了它在促进恶性细胞的生长和增殖中所起的作用之外。 因此，本建议旨在更好地理解SCCUADT的发展机制，以便 我们可能会制定有效的策略来治疗癌前病变， carcinoma.为了达到这一最终目标，我们开始提出的实验，将阐明 在致癌物的背景下，形成癌前病变的基本生物学过程 暴露，并确定这些病变进展为浸润性癌症的机制。目标I测试 假设TMEM16A过表达是促进癌发生的早期事件。我们将（A） 确定TMEM16 A在癌发生的最早阶段是否过表达，以及（B）鉴定TMEM16 A的分子 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点 致癌物诱导的SCCUADT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 TMEM16A在癌前病变中的表达水平表征了进展为侵袭性转移的风险增加。 癌第二，我们将扩展这些研究，剖析调节细胞凋亡的分子机制。 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 过程我们还采用了最先进的启动子占用分析，以确定哪些转录因子， 驱动TMEM16A表达式。 目的II测试致癌作用是由氧化应激（活性氧）水平升高引发的模型 物种，ROS），其最终触发失控循环，导致TMEM16A增加和不受控制的 增长在这个目的中，我们将（A）确定由TMEM 16 A激活的信号通路和（B）确定由TMEM 16 A激活的信号通路。 确定TMEM16A抑制是否将用于治疗发育异常的治疗策略。我们推测 增加的ROS导致NRF2信号传导的上调。NRF2用于增加TMEM16A转录， 最终促进有丝分裂信号传导。使用新的敲除小鼠模型，我们将确定TMEM16A是否 是致癌所必需的。最后，我们使用药理学抑制剂靶向TMEM16A，并暗示它是 一个新的治疗靶点。 在拟议的供资周期结束时，我们计划确定TMEM16A在以下过程中的作用： UADT的致癌作用。我们认为，这些信息将揭示有价值的见解，生物学， 研究不足的疾病，并确定可能最终预防癌症发展的新靶点。

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.