Herpes Viral Targeting of Oral Cancer

描述（由申请人提供）：口腔癌患者常规治疗的结果在30多年来没有显著改善。复发性和不可切除的口腔癌患者的治疗选择很少。我们的患者需要新的治疗方法来改善结果。疱疹溶瘤病毒是一类新的药物，在临床前研究中已证明在治疗口腔癌方面具有有效的治疗效果。这些病毒已被减毒以安全应用，并已达到I期临床试验，取得了令人鼓舞的结果。我们的研究小组已经多次发现这些病毒具有非凡的能力，可以特异性地感染选定的癌症，同时保留正常组织。这些观察结果的机制尚不清楚。尽管我们的溶瘤病毒中的某些基因缺失可能促进肿瘤组织中的优先病毒复制，但它们不能解释优先病毒结合、病毒进入和立即早期基因表达的观察结果。我们的初步研究已经确定了口腔癌细胞糖蛋白D（gD）HSV受体的差异表达作为疱疹溶瘤疗效的重要决定因素。一种受体nectin-1与成功的溶瘤HSV进入靶癌细胞和随后的细胞裂解特别高度相关。Nectin-1也是细胞间粘附连接（AJ）的重要组成部分，其在正常细胞-细胞相互作用中是关键的。AJ在口腔癌中经常通过上皮-间充质转化（EMT）过程抑制E-钙粘蛋白而失调。EMT是癌症进展中的重要事件，其失调正常上皮组织并促进侵袭和转移。我们的初步数据表明，EMT可能与nectin-1的释放，增加nectin-1的可用性，以及对溶瘤疱疹病毒治疗的自然易感性直接相关。我们提出的实验旨在阐明EMT和口腔癌细胞表面nectin-1作为疱疹溶瘤治疗的功能性受体的暴露之间的关系。这些研究将：（1）检测疱疹gD受体和粘附连接组分在正常口腔粘膜、异型增生和癌上的天然表达，（2）研究调节EMT和E-钙粘蛋白对nectin-1表达及其作为疱疹病毒受体的功能的影响，及（3）确定该等对连结的影响是否─ 1和其他HSV受体可能解释了这些溶瘤疱疹病毒在体内的差异靶向能力的观察结果。这些研究有可能（1）将癌症进展的基本过程与对治疗性疱疹载体的天然易感性联系起来，（2）促进病毒结合和进入的新概念（而不是病毒复制）作为溶瘤病毒功效的重要决定因素，以及（3）阐明了新的肿瘤标志物的疱疹溶瘤易感性，可用于选择患者与口腔癌招募即将到来的这些有前途的生物制剂的临床试验。公共卫生相关性：临床前研究表明，许多口腔癌是疱疹溶瘤病毒治疗的敏感靶点。该提案探讨了口腔癌细胞可能自然表达比正常细胞更高水平的疱疹包膜糖蛋白受体的特定机制，从而允许更有选择性地感染和破坏口腔癌细胞。该提案的结果将（1）促进对疱疹病毒如何靶向癌细胞的新理解，（2）确定可用于预测对疱疹溶瘤治疗反应的肿瘤标志物，并可用于指导即将进行的临床试验中的患者选择。

DESCRIPTION (provided by applicant): Outcomes from conventional therapy of patients with oral cancer have not significantly improved in over 30 years. There are few therapeutic options for patients with recurrent and unresectable oral cancers. Our patients need novel therapies to improve outcomes. Herpes oncolytic viruses are a new class of agents that have demonstrated potent therapeutic effects in treating oral cancers in preclinical studies. These viruses have been attenuated for safe application, and have reached phase I clinical trials with encouraging results. Our group has repeatedly identified a remarkable ability by these viruses to specifically infect selected cancers while preserving normal tissues. The mechanisms for these observations are unknown. Although certain genetic deletions within our oncolytic viruses might promote preferential viral replication in tumor tissues, they do not account for observations of preferential viral binding, viral entry and immediate-early gene expression. Our preliminary studies have identified the differential expression of glycoprotein D (gD) HSV receptors by oral cancer cells as an important determinant of herpes oncolytic efficacy. One receptor, nectin-1, is particularly highly correlated with successful oncolytic HSV entry into target cancer cells and subsequent cell lysis. Nectin-1 also serves as an important component of intercellular adherens junctions (AJ's), which are critical in normal cell-cell interactions. AJ's are frequently dysregulated in oral cancers through the repression of E-cadherin by a process called epithelial-mesenchymal transition (EMT). EMT is an important event in cancer progression that dysregulates normal epithelial organization and promotes invasion and metastasis. Our preliminary data suggest that EMT may be directly linked to the liberation of nectin-1, increased nectin-1 availability, and natural susceptibility to oncolytic herpes viral therapy. We propose experiments designed to elucidate the relationships between EMT and the exposure of oral cancer cell surface nectin-1 as a functional receptor to herpes oncolytic therapy. These studies will: (1) examine the natural expression of herpes gD receptors and adherens junctions components on normal oral mucosa, dysplasia, and carcinomas, (2) study the effect of modulation EMT and E-cadherin on nectin-1 expression and its function as a herpes viral receptor, and (3) determine if such effects on nectin-1 and other HSV receptors may account for observations of differential targeting ability by these oncolytic herpes viruses in vivo. These studies have a potential to (1) link a fundamental process of cancer progression with natural susceptibility to therapeutic herpes vectors, (2) promote a novel concept of viral binding and entry (rather than viral replication) as an important determinant of oncolytic viral efficacy, and (3) elucidate novel tumor markers of herpes oncolytic susceptibility that can be used to select patients with oral cancers for enrollment in upcoming clinical trials with these promising biological agents. PUBLIC HEALTH RELEVANCE: Preclinical studies have suggested that many oral cancers are susceptible targets to herpes oncolytic viral therapy. This proposal explores the specific mechanisms by which oral cancer cells may naturally express higher levels of receptors to herpes envelope glycoproteins than normal cells, permitting more selective infection and destruction of oral cancer cells. The results from this proposal will (1) promote a new understanding of how herpes viruses target cancer cells, and (2) identify tumor markers that can be used to predict response to herpes oncolytic therapy, and that can be used to guide patient selection in upcoming clinical trials.