Targeting Adenovirus Vectors to Ovarian Cancer

将腺病毒载体靶向卵巢癌

• 批准号: 6781613
• 负责人: C. RICHTER KING
• 金额: $ 23.5万
• 依托单位: GENVEC, INC.
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-04-01 至 2006-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6781613
• 关键词: Adenoviridae; Coxsackievirus; antineoplastics; cell line; cisplatin; disease /disorder model; female; gene delivery system; gene mutation; gene therapy; genetic markers; integrins; laboratory mouse; nonhuman therapy evaluation; ovary neoplasms; polymerase chain reaction; receptor binding; toxicant screening; transfection; transfection /expression vector; tumor necrosis factor alpha; virus receptors; xenotransplantation

DESCRIPTION (provided by applicant): Despite significant improvements in the management of ovarian cancer, approximately 13,900 women per year in the United States are expected to ultimately fail standard therapies and die. Peritoneal spread is the major route of dissemination and leads to significant morbidity. Therefore, ovarian cancer is well suited for the application of adenoviral anti-cancer treatments because they permit a regional administration of the vector into the peritoneal cavity with exposure of disseminated lesions to a locally high concentration of vector. However, a major disadvantage of current adenovirus vectors is that they efficiently transduce non-target, mesothelial cells that line all the major organs in the peritoneal cavity while inefficiently transducing ovarian cancer cells. This suboptimal efficiency and specificity results because the target cancer cells often do not express high levels of the primary adenovirus receptor, the Coxsackie-Adenovirus Receptor (CAR), while the non-target mesothelial cells are efficiently transduced in a CAR-dependent manner. We have made significant strides in increasing the specificity of adenovirus vectors for cancer applications. We have created two targeted adenovirus vectors that are simultaneously mutated to avoid binding to CAR and genetically redirected for binding to either alphavbeta3/5 or alphavbeta6 integrin receptors, which are both highly expressed in ovarian cancers. Our preliminary data indicates that these vectors will avoid CAR-mediated gene transfer to healthy mesothelial tissue while efficiently targeting tumor cells that express either alphavbeta3/5 or alphavbeta6 integrin receptors. Our overall objective in the proposed studies is to identify a targeted lead vector expressing the therapeutic transgene for tumor necrosis factor-alpha (TNF) for the treatment of ovarian cancer. This lead must demonstrate significant anti-tumor activity with an acceptable toxicity profile in at least 2 preclinical models designed to closely mimic the clinical application. We will first test the hypothesis that the in vitro and in vivo efficiency and specificity of gene delivery are improved through targeting using vectors carrying marker genes (Specific Aim 1). We will then construct alphavbeta3/5 or alphavbeta6 -targeted vectors carrying the transgene for TNF. We will test the feasibility of these vectors as clinical leads by determining whether they display appropriate anti-tumor activities and toxicity profiles according to predefined criteria (Specific Aim 2).

描述（由申请人提供）：尽管卵巢癌的管理有了显着改善，但预计美国每年约有13,900名妇女最终将失败标准疗法并死亡。腹膜扩散是传播的主要途径，导致明显的发病率。因此，卵巢癌非常适合应用腺病毒抗癌治疗，因为它们允许将载体的区域给药到腹膜腔中，并暴露于散布的病变中，向局部高浓度的载体施加。然而，当前腺病毒载体的主要缺点是它们有效地转导非靶向的间皮细胞，这些细胞将腹膜腔中所有主要器官排列在一起，同时降低了卵巢癌细胞。这种次优效率和特异性结果是因为目标癌细胞通常不会表达高水平的原发性腺病毒受体，Coxsackie-Adenovirus受体（CAR），而非目标的间皮细胞则以CAR依赖性方式有效地传递。我们在提高腺病毒载体对癌症应用的特异性方面取得了长足的进步。我们创建了两个靶向腺病毒载体，它们同时突变以避免与CAR结合，并在遗传上重定向以与Alphavbeta3/5或Alphavbeta6整合蛋白受体结合，它们在卵巢癌中都高度表达。我们的初步数据表明，这些载体将避免CAR介导的基因转移到健康的间皮组织，同时有效地靶向表达alphavbeta3/5或alphavbeta6整合蛋白受体的肿瘤细胞。我们在拟议的研究中的总体目标是确定靶向铅载体表达用于治疗卵巢癌的肿瘤坏死因子-Alpha（TNF）的治疗转基因。在至少2个旨在紧密模仿临床应用的临床前模型中，该铅必须表现出显着的抗肿瘤活性，具有可接受的毒性特征。我们将首先检验以下假设：通过使用带有标记基因的矢量靶向，体外和体内效率和基因递送的特异性得到提高（特定目标1）。然后，我们将构建Alphavbeta3/5或载有TNF转基因的Alphavbeta6键入的向量。我们将根据预定义的标准确定它们是否显示出适当的抗肿瘤活性和毒性特征（特定的AIM 2）来测试这些向量作为临床引线的可行性。