Radiation Enhancement of HSV Anti-Tumor Effects

该项目的总体目标是使用新型突变HSV-1改善恶性胶质瘤的治疗 早期的研究表明，电离辐射（IR）激活晚期HSV-1基因的表达， 病毒复制和增强Ayi34.5 HSV的治疗价值。有证据表明， Ayi34.5HSV有效性依赖于肿瘤细胞基因表达，我们鉴定了关键宿主基因， 克服病毒复制限制的MEK。项目1构建了一种突变病毒（R2660）， 一种克服肿瘤对HSV耐药性的放射诱导型组成型作用MEK（caMEK）基因。在Aim中 1，我们建议确定用于病毒生长的MEK基因的最佳表达的辐射剂量， 肿瘤破坏并表征caMEK表达的持续时间。我们还将确定 通过连续IR给药维持肿瘤床中的病毒复制。最后，我们建议 改进/优化晚期病毒启动子放射诱导。在目标2中，我们建议完成以下分析： 恶性胶质瘤患者的基因表达和临床结果数据库，以建立基因表达 描述人类恶性胶质瘤放射抗性的基因表达谱（GEP）。我们确认了至少三个 一组基因，当过度表达时，使肿瘤对IR产生抗性。 161例神经胶质瘤患者的数据库表明，这三种基因组中任何一种的过度表达与 治疗效果很差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细胞系， 目前可用，并将由项目3目标1建立。每个肿瘤细胞系的特征在于 尊重GEP。然后将GEP模式与肿瘤对病毒的易感性相关联 复制，放射敏感性和肿瘤破坏的联合治疗。目标3的目标是 确定用表达caMEK的病毒（R2660）+ IR治疗是否对所有恶性肿瘤有效。 神经胶质瘤我们建议识别在基因表达方面不同的肿瘤簇， 使肿瘤对IR难治的过表达基因集，并评估这些肿瘤对IR的反应。 我们的目标是（i）确定目前可用的治疗性HSV是否将被用于治疗性治疗。 有效对抗广谱恶性神经胶质瘤肿瘤，（ii）以确定GEP是否可以预测， 肿瘤对治疗是难治的，以及（iii）对于与对R2660的抗性相关的GEP谱， + IR，以确定新的目标，以克服在建设改进的治疗性病毒的项目1。 相关性（参见说明）： 项目2是一个高度互动的计划项目赠款的组成部分，旨在提高成果 神经胶质瘤的患者。MEK的作用将被用于这一目的。

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.