Herpes Viral Targeting of Oral Cancer

描述（由申请人提供）：30多年来，口腔癌患者的常规治疗结果没有显著改善。对于复发性和不可切除的口腔癌患者，很少有治疗选择。我们的病人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，在治疗口腔癌的临床前研究中显示出强有力的治疗效果。为了安全应用，这些病毒已被减毒，并已进入I期临床试验，结果令人鼓舞。我们的研究小组反复发现，这些病毒具有一种非凡的能力，可以特异性地感染选定的癌症，同时保留正常组织。这些观测的机制尚不清楚。虽然溶瘤病毒中的某些基因缺失可能促进肿瘤组织中优先的病毒复制，但它们不能解释观察到的优先病毒结合、病毒进入和即时早期基因表达。我们的初步研究已经确定了糖蛋白D (gD) HSV受体在口腔癌细胞中的差异表达是疱疹溶瘤效果的重要决定因素。其中一种受体，连接素-1，与溶瘤性HSV成功进入靶癌细胞和随后的细胞裂解高度相关。Nectin-1也是细胞间粘附连接（AJ's）的重要组成部分，这在正常的细胞-细胞相互作用中至关重要。在口腔癌中，AJ经常通过上皮-间质转化（EMT）过程中e -钙粘蛋白的抑制而失调。EMT是癌症进展中的一个重要事件，它调节了正常上皮组织并促进了侵袭和转移。我们的初步数据表明，EMT可能与nectin-1的释放、nectin-1可用性的增加以及对溶瘤性疱疹病毒治疗的天然易感性直接相关。我们提出了旨在阐明EMT与口腔癌细胞表面连接素-1作为功能性受体暴露于疱疹溶瘤治疗之间的关系的实验。这些研究将：(1)检查疱疹gD受体和粘附连接成分在正常口腔黏膜、发育不良和癌中的自然表达；(2)研究调节EMT和E-cadherin对nectin-1表达的影响及其作为疱疹病毒受体的功能；(3)确定这种对nectin-1和其他HSV受体的影响是否可以解释这些溶瘤性疱疹病毒在体内的不同靶向能力。这些研究有可能(1)将癌症进展的基本过程与治疗性疱疹载体的自然易感性联系起来，(2)促进病毒结合和进入（而不是病毒复制）作为溶瘤病毒疗效的重要决定因素的新概念，以及(3)阐明疱疹溶瘤易感性的新肿瘤标志物，可用于选择口腔癌患者参加即将进行的临床试验，这些有前途的生物制剂。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易感靶点。本研究探讨了口腔癌细胞比正常细胞自然表达更高水平的疱疹包膜糖蛋白受体的具体机制，从而允许更多的选择性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.