Improving Gene Therapy for Superficial Bladder Cancer

改善浅表性膀胱癌的基因治疗

• 批准号: 7729508
• 负责人: WILLIAM Francis BENEDICT
• 金额: $ 18.4万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-01 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7729508
• 关键词: Adenovirus Vector; Aftercare; Annexins; Antibodies; Apoptosis; Binding Proteins; Biological; Biological Assay; Bladder; Bladder Neoplasm; Bypass; Bystander Effect; Cancer cell line; Caspase; Cell Death; Cells; Clinical Research; Clinical Trials; Consultations; Cystectomy; Data; Development; Dose; Enzyme-Linked Immunosorbent Assay; Evolution; Fractionation; Funding; Future; Gene Transfer; Goals; Grant; Growth; Guidelines; Human; Interferon-alpha; Interferons; Intravesical Instillation; Leadership; Malignant neoplasm of urinary bladder; Maps; Mass Spectrum Analysis; Measures; Mediating; Modeling; Molecular; Monitor; Nude Mice; Organ; Patients; Phagocytes; Pharmacodynamics; Phase I Clinical Trials; Phosphatidylserines; Play; Pliability; Principal Investigator; Proteins; Recombinant Interferon; Recombinants; Recording of previous events; Refractory; Reproduction spores; Research Personnel; Resistance; Role; Schedule; Secondary to; Small Interfering RNA; Surrogate Markers; TNFSF10 gene; Techniques; Time; Transitional Cell Carcinoma; Urine; Urothelial Cell; adenoviral-mediated; base; cancer cell; caspase-3; disease natural history; experience; gene therapy; improved; interest; intravesical; neoplastic cell; novel; pre-clinical; programs; research study; transduction efficiency; transgene expression; tumor

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.

在第一轮SPORE资助中，我们开发了一种新颖的、可重复的人类浅表膀胱模型， 无胸腺小鼠的癌症。利用该模型，我们证明了基因转移和膀胱内灌注的功效。 当腺病毒载体与Syn 3（Ad-IFN-α/Syn 3）一起施用时，干扰素-α基因治疗。我们 结果表明，Ad-IFN-α/Syn 3可诱导某些人膀胱癌中caspase-3的活化和凋亡 细胞对重组IFNa蛋白不敏感，并且细胞死亡通过直接和间接途径发生， （旁观者）效应。此外，正常尿路上皮细胞似乎对Ad-IFN-α/Syn 3有抗性。虽然 Ad-IFN-α/Syn 3作用的确切机制尚不清楚， 有足够的说服力来启动第一阶段的研究，该研究计划于2005年第四季度开始。在 我们建议通过这一更新来确定Ad-IFN-α介导其抗肿瘤活性的独特机制。 我们还建议开发基于尿的药效学标记物，使我们能够跟踪生物学特征。 Ad-IFN-o/Syn 3的活性，关注可溶性膜联蛋白1水平的增加与 转导效率、肿瘤细胞凋亡或两者。最后，通过使用一个优雅的整体器官映射， 我们的同事在项目1中开发的技术，我们建议准确地映射表达 干扰素-a，在第一阶段试验之后的原理验证实验中。为此，我们建议3 具体目标。(1)目的探讨annexin-1在腺病毒干扰素（Ad-IFN）诱导的细胞凋亡中的作用。(2)识别 Ad-IFN诱导的旁观者效应的分子机制。(3)评价转基因 膀胱灌注后IFN-α的表达和Ad-IFN/Syn 3的活性 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个新的范例， 这可能会从本质上改变这种疾病的自然史。