Mechanisms of Resistance to Radio Inducible Gene Therapy

描述（由申请人提供）：这个项目的目标是探索Ad的机制。Egr-TNF基因治疗可增强肿瘤对放疗的反应。我们报道了电离辐射（IR）靶向基因治疗在辐射诱导启动子（Egr-1）的控制下，通过激活编码肿瘤坏死因子- α (tnf - α)的cDNA表达来增强放射治疗的抗肿瘤作用。小鼠和人肿瘤模型均证实了Ad的激活。Egr-TNF在单次或分次放射后达到肿瘤内tnf - α蛋白的治疗浓度。与Ad联合治疗。与单独治疗相比，Egr-TNF和IR显著增加了这些肿瘤模型的肿瘤消退和治愈率，而正常组织毒性很少或没有增加。广告。Egr-TNF在两项1期临床试验证明安全性后，目前正在进行3项2期临床试验的放射治疗研究。分期试验的治疗效果表明，约20%的放射耐药（黑色素瘤、肉瘤、直肠癌）或非常大的肿瘤（高达13,500 cm3）患者获得了完全缓解，迄今为止没有复发的证据。本文概述的实验将采用遗传和药理学模型来探索AD的抗肿瘤机制。Egr-TNF和IR为合理提高这种新型联合治疗方式的疗效提供实验依据。为实现这些目标，我们提出以下具体目标。

DESCRIPTION (provided by applicant): The goal of this project is to explore the mechanisms by which Ad.Egr-TNF gene therapy enhances the response of tumors to radiotherapy. We have reported that gene therapy targeted by ionizing radiation (IR) enhances the anti-tumor effects of radiotherapy by activating the expression of a cDNA encoding tumor necrosis factor-alpha (TNF-alpha) under the control of a radiation-inducible promoter (Egr-1). Murine and human tumor models demonstrate activation of Ad.Egr-TNF following single dose or fractionated radiation and achieves therapeutic concentrations of intratumoral TNF-alpha protein. Combined treatment with Ad.Egr-TNF and IR significantly increased tumor regression and cures in these tumor models compared with either treatment alone with little or no increase in normal tissue toxicity. Ad.Egr-TNF is currently being investigated with radiation therapy in three Phase 2 clinical trials following demonstration of safety in two Phase 1 trials. Treatment efficacy in the phase trials was suggested by the fact that > 20% patients with radioresistant (melanoma, sarcoma, rectal cancer) or very large tumors (up to 13,500 cm3) achieved complete responses and are without evidence of recurrence to date. Experiments outlined here will employ genetic and pharmacological models to explore the anti-tumor mechanisms of AD.Egr-TNF and IR to provide the experimental basis to rationally improve the efficacy of this new combined modality treatment. To achieve these goals we propose the following specific aims. Specific Aim 1. Explore whether the tumor microvascular endothelium mediates resistance to Ad.Egr-TNF and IR. Specific Aim 2. Explore whether the tumor secretion of vascular endothelial growth factor (VEGF) mediates resistance to Ad.Egr-TNF +IR by enhancing resistance of the tumor endothelium. Specific Aim 3. Explore the role of tumor cell resistance to Ad.Egr-TNF+IR.