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）：尽管卵巢癌的治疗取得了显着进步，但预计美国每年约有 13,900 名女性最终因标准治疗失败而死亡。腹膜传播是主要的传播途径并导致显着的发病率。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局部施用到腹膜腔中，并使播散性病变暴露于局部高浓度的载体。然而，当前腺病毒载体的一个主要缺点是它们能有效转导腹膜腔内所有主要器官内的非靶标间皮细胞，而不能有效转导卵巢癌细胞。这种次优的效率和特异性是因为靶癌细胞通常不表达高水平的初级腺病毒受体柯萨奇腺病毒受体 (CAR)，而非靶标间皮细胞以 CAR 依赖性方式有效转导。我们在提高腺病毒载体在癌症应用中的特异性方面取得了重大进展。我们创建了两种靶向腺病毒载体，它们同时发生突变以避免与 CAR 结合，并进行基因重定向以与 alphavbeta3/5 或 alphavbeta6 整合素受体结合，这两种受体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 介导的基因转移至健康间皮组织，同时有效靶向表达 alphavbeta3/5 或 alphavbeta6 整联蛋白受体的肿瘤细胞。我们在拟议研究中的总体目标是确定表达肿瘤坏死因子-α（TNF）治疗转基因的靶向先导载体，用于治疗卵巢癌。该先导药物必须在至少 2 个旨在密切模拟临床应用的临床前模型中表现出显着的抗肿瘤活性和可接受的毒性特征。我们将首先测试以下假设：通过使用携带标记基因的载体进行靶向，可以提高基因递送的体外和体内效率和特异性（具体目标 1）。然后我们将构建携带 TNF 转基因的 alphavbeta3/5 或 alphavbeta6 靶向载体。我们将根据预定义的标准（具体目标 2）确定这些载体是否表现出适当的抗肿瘤活性和毒性特征，从而测试这些载体作为临床先导药物的可行性。