DNA Damage Targeted Gene Therapy in Head & Neck Cancer

描述（由申请人提供）：头颈部鳞状细胞癌（H&N）是一种常见的恶性肿瘤。现有的治疗导致不满意的生存，并与过度的毒性。该项目的目标是确定更一致的疗效和毒性较小的治疗方法。本项目将评价在研究Ad.Egr-TNF. 11 D（TNFerade，GenVec）与标准放疗（XRT）或放化疗（CT/XRT）联合给药时，肿瘤血管系统和/或肿瘤细胞是否为靶点。Ad.Egr-TNF. 11 D是E1、E2、E3缺失的腺病毒载体，其编码人TNF-α cDNA上游的放射诱导型启动子，人TNF-α是一种具有强效抗肿瘤和放射增敏作用的细胞因子，通过血管坏死和血栓形成介导。我们将研究干扰素信号通路的主要上游成分STAT 1是否是对Ad.Egr-TNF. 11 D/XRT或CT耐药的预测因子，并代表未来潜在的XRT调节研究靶点。目的1A将研究在临床I/III期试验中向标准XRT中添加Ad.Egr-TNF. 11 D当给予具有晚期H&N癌症的低风险患者时是否安全和有效。目的1B将研究该药物与CT/XRT联合治疗局部复发的既往放疗过的H&N癌患者。目的1C将评估在治疗前和治疗期间收集的活检标本中注射Ad.Egr-TNF. 11 D和XRT后肿瘤微环境内TNF-α蛋白的局部诱导。目标2将直接聚焦于肿瘤细胞。在这里，我们将进一步探讨以前的观察表明，STAT 1过表达与内在的肿瘤细胞耐药。目的3：肿瘤动物模型的相关影像学研究。将进行MRI测量，以检测ad.Egr-TNF. 11 D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疗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.