Radiation Enhancement of HSV Anti-Tumor Effects

这个项目的总体目标是使用新的HSV-1突变株来改善恶性胶质瘤的治疗 早期的研究表明，电离辐射(IR)激活了晚期HSV-1基因的表达，使更好地 病毒复制和增强Ayi 34.5 HSV的治疗价值。针对有证据表明 Ayi 34.5HSV的疗效依赖于肿瘤细胞基因的表达，我们发现了一个关键的宿主基因， MEK克服了对病毒复制的限制。项目1构建了一种携带有 一种可放射诱导的结构性作用MEK(CaMEK)基因，可克服肿瘤对HSV的耐药性。在AIM 1，我们建议确定MEK基因最佳表达的辐射剂量，以促进病毒生长和 肿瘤破坏，并表征caMEK表达的持续时间。我们还将确定以下可行性： 通过连续的IR给药维持肿瘤床中的病毒复制。最后，我们建议 改善/优化晚期病毒启动子的辐射诱导性。在目标2中，我们建议完成以下分析 恶性胶质瘤患者基因表达数据库和临床结果以建立基因表达 人类恶性胶质瘤放射抗性的特征。我们确认了至少三个 一组基因，当过度表达时，使肿瘤对IR产生抗药性。初步研究使用单一的 161名患者的胶质瘤数据库表明，这三组基因中的任何一组的过度表达都与 治疗反应不佳。我们将使用多个数据库来识别恶性胶质瘤GEP 与对治疗的不同反应有关。在目标3中，我们计划研究恶性胶质瘤系，两者 目前是可用的，并将由项目3目标1建立。每个肿瘤株将具有 尊重GEP。GEP模式将与肿瘤对病毒的易感性相关 复制、辐射敏感性和联合治疗对肿瘤的破坏。目标3的目标是 确定CaMEK表达病毒(R2660)+IR治疗对所有恶性肿瘤是否有效 神经胶质瘤。我们建议识别在基因表达方面不同的肿瘤簇，并识别 使肿瘤对IR不敏感的过度表达的基因集并评估这些肿瘤对IR的反应 治疗性病毒+IR。我们的目标是(I)确定目前可用的治疗性HSV是否将 对广泛的恶性胶质瘤有效，(Ii)确定GEP是否可以预测 肿瘤将难以治疗，以及(Iii)与R2660耐药相关的GEP图谱 +IR，以确定项目1在构建改进的治疗性病毒时要克服的新目标。 相关性(请参阅说明)： 项目2是旨在改善结果的高度互动计划项目赠款的组成部分 神经胶质瘤患者的比例。为实现这一目标，将利用MEK的作用。

The overall goal of this project is to improve treatment of malignant gliomas using novel mutant HSV-1 Earlier studies showed that ionizing radiation (IR) activates expression of late HSV-1 genes, enabling better viral replication and enhancing the therapeutic value of Ayi34.5 HSV. In response to evidence that the effectiveness of Ayi34.5HSV is dependent on tumor cell gene expression, we identified a key host gene, MEK that overcomes the restriction to viral replication. Project 1 constructed a mutant virus (R2660) carrying a radio-inducible constitutively-acting MEK (caMEK) gene that overcomes tumor resistance to HSV. In Aim 1, we propose to determine the radiation dose for optimum expression of the MEK gene for virus growth and tumor destruction and to characterize duration of caMEK expression. We also will determine feasibility of sustaining viral replication in the tumor bed by serial IR administration. Lastly, we propose to improve/optimize radio-inducibility of late viral promoters. In Aim 2, we propose to complete analyses of malignant glioma patient databases of gene expression and clinical outcome to establish Gene Expression Profiles (GEP) that characterize radioresistance in human malignant gliomas. We identified at least three sets of genes which, when over-expressed, render tumors resistant to IR. Preliminary studies using a single glioma data base of 161 patients indicated that over-expression of any of these three gene sets correlates with a poor therapeutic response. We will use multiple databases to identify malignant glioma GEP that are associated with differential responses to therapy. In Aim 3, we plan to study malignant glioma lines, both currently available and to be established by Project 3 Aim 1. Each tumor line will be characterized with respect to GEP. GEP patterns will then be correlated with respect to susceptibility of tumors to virus replication, radiation sensitivity and tumor destruction by combined therapy. The objective of Aim 3 is to determine whether treatment with caMEK expressing virus (R2660) + IR is effective against all malignant gliomas. We propose to identify clusters of tumors that differ with respect to gene expression and to identify over-expressed gene sets that render tumors refractory to IR and to evaluate responses of these tumors to therapeutic viruses + IR. Our goals are (i) to determine whether currently available therapeutic HSV will be effective against a broad spectrum of malignant glioma tumors, (ii) to determine whether GEPs can predict if a tumor will be refractory to treatment, and (iii) for GEP profiles that are associated with resistance to R2660 + IR, to identify novel targets to overcome in construction of improved therapeutic viruses by Project 1. RELEVANCE (See instructions): Project 2 is a component of a highly interactive Program Project Grant that is designed to improve outcome of patients with gliomas. The role of MEK will be exploited toward this end.