Improving Gene Therapy for Superficial Bladder Cancer

在第一个孢子资助周期中，我们开发了一种新的、可重复使用的人类浅表膀胱模型。 无瘤小鼠的癌症。通过这个模型，我们展示了基因转移和膀胱内注射的疗效。 腺病毒载体携带Syn3的干扰素-α基因治疗(Ad-干扰素-α/Syn3)。我们 结果表明，Ad-干扰素-a/Syn3可诱导部分人膀胱癌caspase-3的激活和凋亡 对重组IFNA蛋白不敏感且通过直接和间接方式发生细胞死亡的细胞 (旁观者)效果。此外，正常的尿路上皮细胞似乎对Ad-干扰素-a/Syn3具有抵抗力。尽管 Ad-干扰素-oc/Syn3作用的确切机制尚不清楚，临床前数据为 足以令人信服地启动第一阶段研究，计划于2005年第四季度开始。在……里面 在这次更新中，我们建议定义Ad-干扰素-a介导其抗肿瘤活性的独特机制。 我们还建议开发基于尿液的药效学标记，使我们能够跟踪生物 Ad-干扰素-o/Syn3的活性，重点关注可溶性膜联蛋白1水平增加与 转导效率，肿瘤细胞凋亡，或两者兼而有之。最后，通过使用优雅的整体器官映射 技术，我们在项目1中建议准确地映射 干扰素-a，在I期试验之后的原则验证实验中。为此，我们建议3 明确的目标。(1)明确Annexin-1在Ad-干扰素诱导细胞凋亡中的作用。(2)识别 Ad-干扰素诱导旁观者效应的分子机制。(3)评价转基因 小鼠膀胱内灌注后干扰素-α的表达及Ad-干扰素/Syn3活性的变化 尿路上皮癌患者 这些研究有可能为浅表性膀胱癌的治疗建立一种新的范式， 这可能会从本质上改变这种疾病的自然历史。

In the first cycle of SPORE funding, we developed a novel, reproducible, model for human superficial bladder cancer in athymic mice. With this model we demonstrated gene transfer and efficacy of intravesical interferon-a gene therapy when the adenoviral vector was administered with Syn3 (Ad-IFN-a/Syn3). We showed that Ad-IFN-a/Syn3 induced caspase-3 activation and apoptosis in some human bladder cancer cells that were insensitive to recombinant IFNa protein and that cell death occurred via direct and indirect (bystander) effects. Moreover, normal urothelial cells appear to be resistant to Ad-IFN-a/Syn3. Although the exact mechanisms underlying the effects of Ad-IFN-oc/Syn3 are unknown, the preclinical data were compelling enough to launch a Phase I study, which is scheduled to open in the fourth quarter of 2005. In this renewal we propose to define the unique mechanisms by which Ad-IFN-a mediates its antitumor activity. We also propose to develop pharmacodynamic urine-based markers that will allow us to track the biological activity of Ad-IFN-o/Syn3, focusing on the possibility that increased levels of soluble annexin 1 correlate with transduction efficiency, tumor cell apoptosis, or both. Finally, by using an elegant whole organ mapping technique developed by our colleagues in Project 1, we propose to accurately map the expression of interferon-a, in a proof-of-principle experiment that will follow the Phase I trial. To this end, we propose 3 Specific Aims. (1) To define the role of annexin-1 in apoptosis induced by Ad-IFN. (2) To identify the molecular mechanisms involved in the Ad-IFN-induced bystander effect. (3) To evaluate transgene expression of IFN-a and the activity of Ad-IFN/Syn3 following intravesical instillation into the bladder of patients with urothelial carcinoma These studies have the potential to establish a new paradigm for the therapy of superficial bladder cancer, which might qualitatively change the natural history of this disease.