DNA Damage Targeted Gene Therapy in Head & Neck Cancer

描述（由申请人提供）：头颈鳞状细胞癌 (H&N) 是一种常见且使人衰弱的恶性肿瘤。现有的疗法导致生存率不理想，并且与过度毒性有关。该项目的目标是定义疗效更一致、毒性更小的疗法。该项目将在研究 Ad.Egr-TNF.11D（TNFerade，GenVec）与标准放疗（XRT）或放化疗（CT/XRT）一起给予时评估肿瘤脉管系统和/或肿瘤细胞是否是靶标。 Ad.Egr-TNF.11D 是一种 E1、E2、E3 缺失的腺病毒载体，编码人 TNF-α cDNA 上游的放射诱导型启动子，TNF-α 是一种通过血管坏死和血栓形成介导的细胞因子，具有有效的抗肿瘤和放射增敏作用。我们将研究 STAT1（干扰素信号通路的主要上游成分）是否是 Ad.Egr-TNF.11D/XRT 或 CT 耐药性的预测因子，并代表其他 XRT 调制研究的潜在未来目标。目标 1A 将调查在临床 I/I I 期试验中，在标准 XRT 中添加 Ad.Egr-TNF.11D 给患有晚期 H&N 癌症的低风险患者是否安全且有效。目标 1B 将研究使用 CT/XRT 治疗局部复发性既往接受过放射治疗的 H&N 癌症患者的治疗情况。目标 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.11D 和 XRT 后，肿瘤微环境中 TNF-α 蛋白的局部诱导情况。目标 2 将直接关注肿瘤细胞。在这里，我们将进一步探讨先前的观察结果，表明 STAT 1 过度表达与肿瘤细胞内在耐药性相关。目标 3 将重点关注动物肿瘤模型的相关成像研究。将进行 MRI 测量以检测 ad.Egr-TNF.11D 和 XRT 治疗后血流变化和/或血管破坏和细胞死亡。这些研究将带来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.