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）是一种常见的恶性肿瘤。现有的治疗方法导致不理想的生存，并伴有过度的毒性。该项目的目标是确定更一致的疗效和毒性更小的治疗方法。在研究Ad.Egr-TNF时，该项目将评估肿瘤血管系统和/或肿瘤细胞是否为靶标。11D （TNFerade, GenVec）与标准放疗（XRT）或放化疗（CT/XRT）联合给予。Ad.Egr-TNF。11D是一种E1， E2， E3缺失的腺病毒载体，编码人类tnf - α cDNA上游的无线电诱导启动子，tnf - α是一种通过血管坏死和血栓介导的具有强效抗肿瘤和辐射增敏作用的细胞因子。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耐药的预测因子。11D/XRT或CT，代表了未来XRT调制研究的潜在目标。Aim 1A将研究Ad.Egr-TNF的添加是否。在临床I/I期试验中，给晚期H&N癌症的低风险患者11D到标准XRT是安全有效的。Aim 1B将研究该药物与CT/XRT联合应用于局部复发既往放疗的H&N癌患者。Aim 1C将评估注射Ad.Egr-TNF后肿瘤微环境中tnf - α蛋白的局部诱导。治疗前和治疗期间活检标本的11D和XRT。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过表达与肿瘤细胞的内在耐药性有关。目的3将重点关注动物肿瘤模型的相关影像学研究。MRI测量将用于检测ad.Egr-TNF治疗后血流量和/或血管破坏和细胞死亡的变化。11D和XRT。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.