Herpes Viral Targeting of Oral Cancer

疱疹病毒靶向口腔癌

• 批准号: 7659226
• 负责人: Richard J Wong
• 金额: $ 28.49万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-04-01 至 2011-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7659226
• 关键词: Accounting; Adherens Junction; Affect; Attenuated; Binding; Biological Products; Carcinoma; Cell Adhesion Molecules; Cell Communication; Cell Surface Receptors; Cell surface; Cell-Cell Adhesion; Cells; Cellular Morphology; Clinical Trials; Complex; Cytolysis; Data; Dysplasia; E-Cadherin; Engineering; Enrollment; Epithelial; Epithelial Cells; Epithelium; Event; Exposure to; Foundations; Functional disorder; Future; Gene Expression; Genetic; Glycoproteins; Herpesviridae; Human; Immediate-Early Genes; Infection; Investigation; Link; Loss of E-cadherin Expression; MAP Kinase Gene; Malignant - descriptor; Malignant Neoplasms; Measurable; Measures; Memorial Sloan-Kettering Cancer Center; Mesenchymal; Modeling; Neoplasm Metastasis; Normal Cell; Normal tissue morphology; Oncolytic; Oncolytic viruses; Oral; Oral mucous membrane structure; Outcome; PVRL1; Pathway interactions; Patient Selection; Patients; Phase I Clinical Trials; Phenotype; Predisposition; Process; Recurrence; Relative (related person); Reporting; Repression; Safety; Simplexvirus; Therapeutic; Therapeutic Effect; Treatment Efficacy; Tumor Markers; Tumor Tissue; Unresectable; Viral; Virus; Virus Receptors; cancer cell; conventional therapy; design; improved; in vivo; malignant mouth neoplasm; malignant state; mouth squamous cell carcinoma; novel; oncolysis; preclinical study; public health relevance; receptor; research study; response; tumor; tumor progression; tumorigenesis; vector

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.

描述（由申请人提供）： 30 多年来，口腔癌患者的常规治疗结果并未显着改善。对于复发性和不可切除的口腔癌患者来说，治疗选择很少。我们的患者需要新的疗法来改善治疗结果。疱疹溶瘤病毒是一类新型药物，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确保安全应用，并已进入一期临床试验并取得了令人鼓舞的结果。我们的研究小组多次发现这些病毒具有显着的能力，可以特异性感染选定的癌症，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会促进肿瘤组织中的优先病毒复制，但它们并不能解释优先病毒结合、病毒进入和早期基因表达的观察结果。我们的初步研究已确定口腔癌细胞糖蛋白 D (gD) HSV 受体的差异表达是疱疹溶瘤功效的重要决定因素。其中一种受体 nectin-1 与溶瘤 HSV 成功进入靶癌细胞以及随后的细胞裂解高度相关。 Nectin-1 也是细胞间粘附连接 (AJ) 的重要组成部分，这对于正常的细胞间相互作用至关重要。在口腔癌中，AJ 经常通过上皮-间质转化 (EMT) 过程抑制 E-钙粘蛋白而失调。 EMT 是癌症进展中的一个重要事件，它会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、nectin-1 可用性的增加以及对溶瘤疱疹病毒治疗的自然敏感性直接相关。我们提出的实验旨在阐明 EMT 与口腔癌细胞表面 nectin-1 作为疱疹溶瘤治疗的功能受体的暴露之间的关系。这些研究将：(1) 检查正常口腔粘膜、不典型增生和癌上疱疹 gD 受体和粘附连接成分的自然表达，(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，以及 (3) 确定对 nectin-1 和其他 HSV 受体的这种影响是否可以解释差异靶向的观察结果 这些溶瘤疱疹病毒在体内的能力。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自然敏感性联系起来，（2）促进病毒结合和进入（而不是病毒复制）作为溶瘤病毒功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纳入研究 即将对这些有前途的生物制剂进行临床试验。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易感靶标。该提案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，从而可以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认识，以及（2）识别可用于预测对疱疹溶瘤治疗的反应的肿瘤标志物，并可用于指导即将进行的临床试验中的患者选择。