Targeting Adenovirus Vectors to Ovarian Cancer

描述（由申请人提供）：尽管卵巢癌的管理有了显著改善，但预计美国每年约有13，900名妇女最终无法接受标准治疗并死亡。腹膜传播是主要的传播途径，并导致显著的发病率。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，使播散性病变暴露于局部高浓度的载体。然而，目前的腺病毒载体的主要缺点是，它们有效地抑制非靶向间皮细胞，而无效地转导卵巢癌细胞，所述间皮细胞排列在腹膜腔中的所有主要器官中。这种次优效率和特异性的结果是因为靶癌细胞通常不表达高水平的主要腺病毒受体，柯萨奇-腺病毒受体（CAR），而非靶间皮细胞以CAR依赖性方式有效转导。我们在提高腺病毒载体对癌症应用的特异性方面取得了重大进展。我们已经创建了两种靶向腺病毒载体，它们同时突变以避免与CAR结合，并在遗传上重定向以结合α v β 3/5或α v β 6整联蛋白受体，这两种受体在卵巢癌中均高度表达。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α v β 3/5或α v β 6整联蛋白受体的肿瘤细胞。我们的总体目标是在拟议的研究是确定一个有针对性的领导载体表达肿瘤坏死因子α（TNF）的治疗转基因治疗卵巢癌。该电极导线必须在至少2个旨在密切模拟临床应用的临床前模型中证明具有显著的抗肿瘤活性和可接受的毒性特征。我们将首先测试这样的假设，即通过使用携带标记基因的载体靶向，提高了基因递送的体外和体内效率和特异性（特异性目的1）。然后我们将构建携带TNF转基因的α v β 3/5或α v β 6靶向载体。我们将根据预定义的标准（具体目标2），通过确定这些载体是否显示适当的抗肿瘤活性和毒性特征，来测试这些载体作为临床先导药物的可行性。

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).