ICON TARGETING OF TUMOR VASCULATURE AND TUMOR CELLS

一旦上皮肿瘤如乳腺癌和前列腺癌转移并对激素疗法和化学疗法产生耐药性，就没有控制该疾病的有效选择。作为治疗这些和其他恶性肿瘤的一种新方法，我们构建了一种称为Icon的融合蛋白，其由作为靶向结构域的因子VII（fVII）和作为效应结构域的IgG的Fc区组成，该Fc区激活针对肿瘤的溶细胞免疫攻击。 绑定图标的细胞。Icon以特殊的亲和力和特异性结合组织因子（TF），组织因子是fVII的天然受体，在所有实体瘤的血管内皮细胞上表达，但在正常组织中不表达。TF也在恶性肿瘤细胞上表达，为肿瘤血管系统和肿瘤细胞提供靶点。先前在人类肿瘤异种移植模型中的数据显示，肿瘤内注射编码Icon的腺病毒载体可以诱导注射的肿瘤以及未注射的身体其他部位的肿瘤消退。我们现在提出以下具体目标，利用血管治疗计划项目资助的项目和核心，以进一步为癌症治疗做好准备。具体目标1：使用活体显微镜优化用于治疗的Icon的剂量、时间表和最佳递送模式：瘤内注射Icon载体vs尾静脉注射Icon蛋白（活体显微镜检查提供了Icon与肿瘤血管系统结合的选择性和肿瘤血管内皮细胞以及肿瘤细胞的反应的短期数据）;具体目标#2：使用人肿瘤异种移植物模型来优化用于治疗的Icon的剂量、时间表和最佳递送模式：瘤内注射Icon载体对比尾静脉注射Icon蛋白（Icon载体的剂量、时间表和最佳递送模式）。 异种移植物模型提供长期肿瘤反应数据以及关于Icon与肿瘤脉管系统结合的选择性的信息）;具体目标#3：使用自发性癌症的转基因小鼠模型和人组织因子来测试安全性，Icon抑制已发展数月的既定疾病生长的选择性和有效性（而不是像活体显微镜和异种移植模型那样持续数天）， 以及它的传播具体目标#4：研究Icon疗法与其他肿瘤血管靶向治疗组合对肿瘤血管系统和肿瘤细胞的影响，以及研究Icon在结合TF之前引入血流后发生的变化，以及TF/fVII复合物形成后的加工;以及具体目标#5：Icon的一期临床试验如果这些拟议的研究表明Icon在拟议研究的肿瘤中安全有效，则可能将Icon用于依赖于新血管持续生长的许多其他类型的癌症。

Once epithelial neoplasms such as carcinomas of the breast and prostate become metastatic and develop resistance to hormonal therapy and chemotherapy, there are no effective options for the control of the disease. As a novel approach to treat these and other malignancies, we constructed a fusion protein called an Icon, composed of factor VII (fVII) as the targeting domain and the Fc region of IgG as the effector domain that activates a cytolytic immune attack against cells that bind the Icon. The Icon binds with exceptional affinity and specificity to tissue factor (TF), the natural receptor for fVII that is expressed on endothelial cells of the vasculature in all solid tumors but not in normal tissues. TF also is expressed on malignant tumor cells, providing a target for both the tumor vasculature and tumor cells. Previous data in a human tumor xenograft model showed that intratumoral injections of an adenoviral vector encoding the Icon can induce regressions of the injected tumor as well as tumors elsewhere in the body that were not injected. We now propose the following specific aims which take advantage of the projects and cores of the Vascular Therapy Program Project Grant in order to further prepare the Icon for cancer treatment. Specific Aim # 1: Use of intravital microscopy to optimize the dose, schedule and optimal mode of delivery of the icon for therapy: intratumoral injection of the Icon vector vs tail vein injection of the Icon protein (intravital microscopy provides short term data on the selectivity of binding of the Icon to tumor vasculature and response of the tumor vascular endothelial cells as well as the tumor cells); Specific Aim #2: Use of the human tumor xenograft model for the optimization of the dose, schedule and optimal mode of delivery of the Icon for therapy: intratumoral injection of the Icon vector vs tail vein injection of the Icon protein (the xenograft model provides long term tumor response data as well as information on selectivity of binding of the Icon to the tumor vasculature); Specific Aim #3: Use of transgenic mouse models of spontaneous cancer and human Tissue Factor to test the safety, selectivity and efficacy of the Icon for suppressing growth of established disease which has developed over months (rather than over days as is the case with the intravital microscopy and xenograph models) as well as its spread (metastasis) to other organs; Specific Aim #4: Study of the effect of Icon therapy combined with other tumor vascular targeting treatments on the tumor vasculature and the tumor cells as well the study of the changes which occur in the Icon after its introduction into the bloodstream before binding to TF, and the processing of the TF/fVII complex after it is formed; and Specific Aim #5: a Phase I clinical trial of the Icon. If these proposed studies show that the Icon is safe and effective in the neoplasms proposed for study, it may be possible to use the Icon for the many other types of cancers that depend on a neovasculature for continued growth.