DNA Damage Targeted Gene Therapy in Head & Neck Cancer

描述(申请人提供)：头颈部鳞状细胞癌(H&N)是一种常见的、使人衰弱的恶性肿瘤。现有的治疗方法会导致无法令人满意的生存，并伴随着过度的毒性。该项目的目标是定义更一致的疗效和毒性更低的疗法。该项目将在研究Ad.Egr-TNF.11D(TNFerade，GenVec)与标准放射治疗(XRT)或化疗(CT/XRT)一起使用时，评估肿瘤血管和/或肿瘤细胞是否为靶点。Ad.Egr-TNF.11D是一种E1、E2、E3缺失的腺病毒载体，它编码一个辐射诱导的启动子，位于人肿瘤坏死因子基因的上游，人肿瘤坏死因子是一种通过血管坏死和血栓介导的细胞因子，具有很强的抗肿瘤和辐射增敏作用。我们将调查干扰素信号通路的主要上游成分STAT1是否是Ad.Egr-TNF.11D/XRT或CT耐药的预测因子，并代表未来更多XRT调制研究的潜在靶点。目的研究在临床I/I期试验中，将Ad.Egr-TNF.11D添加到标准XRT中，用于低风险晚期H&N癌患者是否安全和有效。目的1B将通过CT/XRT研究该药在既往放疗后局部复发的H&N癌患者中的应用情况。目的1C将评估注射Ad.Egr-TNF.11D和XRT后肿瘤微环境中肿瘤坏死因子-α蛋白的局部诱导，在治疗前和治疗期间收集活检标本。AIM 2将直接聚焦于肿瘤细胞。在这里，我们将进一步探讨先前的观察结果，即STAT1的过度表达与肿瘤细胞的内在耐药性有关。目的3将侧重于动物肿瘤模型的相关影像研究。将进行MRI测量，以检测Ad.Egr-TNF.11D和XRT治疗后血流和/或血管破坏和细胞死亡的变化。这些研究将导致新的治疗方法和未来的临床试验。

DESCRIPTION (provided by applicant): Squamous cell carcinoma of the head and neck (H&N) is a common and debilitating malignancy. Available therapies lead to unsatisfactory survival and are associated with excessive toxicity. The goal of this Project is to define more consistently curative and less toxic therapies. The Project will evaluate whether the tumor vasculature and/or tumor cells are targets when investigating Ad.Egr-TNF.11D (TNFerade, GenVec) given together with standard radiotherapy (XRT) or chemoradiotherapy (CT/XRT). Ad.Egr-TNF.11D is an E1, E2, E3 deleted adenoviral vector that encodes a radio-inducible promoter upstream from a cDNA for human TNF-alpha, a cytokine that has potent antitumor and radiation sensitizing effects, mediated via vascular necrosis and thrombosis. We will investigate whether STAT1, a principal upstream component of the interferon signaling pathway is a predictor of resistance to Ad.Egr-TNF.11D/XRT or CT and represents a potential future target for additional XRT modulation research. Aim 1A will investigate whether the addition of Ad.Egr-TNF.11D to standard XRT is safe and active when given to poor-risk patients with advanced H&N cancer in a clinical phase I/I I trial. Aim 1B will investigate the administration of the agent with CT/XRT in patients with regionally recurrent previously irradiated H&N cancer. Aim 1C will evaluate local induction of TNF-alpha protein within the tumor microenvironment following injection of Ad.Egr-TNF.11D and XRT in biopsy specimens collected prior to and during therapy. Aim 2 will focus directly on the tumor cells. Here we will further explore previous observations suggesting that STAT 1 overexpression is associated with intrinsic tumor cell resistance. Aim 3 will focus on correlative imaging studies in animal tumor models. MRI measurements will be performed to detect changes in blood flow and/or vascular destruction and cell death following treatment with ad.Egr-TNF.11D and XRT. These studies will lead to new therapies and future clinical trials.