Enhanced CRAd for Esophageal Adenocarcinoma

描述（由申请人提供）： 食管腺癌现在是西方男性中增长最快的癌症类别。此外，尽管目前的管理进展，局部晚期疾病的预后仍然保持不变。这些事实清楚地表明，发展新的治疗方法对食管腺癌的必要性。尽管条件复制型腺病毒（CRAd）提供了一种新的和有效的方式来接近胃肠道的实体瘤，食管腺癌细胞是非常耐腺病毒感染，由于腺病毒的主要受体（柯萨奇-腺病毒受体，CAR）的表达最低。此外，缺乏对食管腺癌具有选择性的启动子阻碍了CRAd的构建，CRAd可以在靶肿瘤细胞中选择性复制以实现用于临床用途的有用治疗指数。最后，缺乏A 检测CRAd复制和扩散的非侵入性体内成像方法阻碍了对CRAd体内生物学的理解。为了实现CRAds对食管腺癌的全部治疗潜力，我们提出构建启动子驱动的、具有成像能力的感染性增强的CRAds。为了解决第一个问题，我们已经鉴定了三种有希望的启动子，其表现出有利的“肿瘤与肝脏”和“肿瘤与正常粘膜”差异，这对于在腺病毒环境中的应用是至关重要的。同样，我们已经开发了改变腺病毒的向性的方法，从而实现肿瘤靶细胞的感染性增强。在纤维结区域的HI环中掺入RGD 4C基序和Ad 5/3嵌合纤维修饰已显示出显著提高腺病毒对食管腺癌细胞的感染效力。这些发现为食管腺癌细胞抵抗腺病毒感染的问题提供了解决方案。此外，我们将在我们的感染性增强CRAds中配置光学和放射成像功能，这些CRAds由最佳启动子驱动。这些特征提供了在临床环境中CRAd复制和传播的微创检测，用作与患者安全相关的监测系统。因此，很明显，由最佳启动子元件控制并具有成像能力的感染性增强的CRAds将是对食管腺癌具有很大临床实用性的治疗剂。这些模式的适用性将从毒理学和杀肿瘤作用的观点沿着确定，并通过光学和放射成像确认CRAd功能。

DESCRIPTION (provided by applicant): Esophageal adenocarcinoma is now the fastest growing cancer category in western men. Additionally, the prognosis of locally advanced disease has remained static despite current management advances. These facts clearly indicate the necessity of developing novel therapeutic approaches for esophageal adenocarcinoma. Even though conditionally replicative adenoviruses (CRAds) offer a novel and potent modality to approach solid tumors of the gastrointestinal tract, esophageal adenocarcinoma cells are extremely resistant to adenoviral infection due to minimal expression of the adenoviral primary receptor (coxsackie-adenovirus receptor, CAR). Furthermore, the lack of promoters with selectivity for esophageal adenocarcinoma has hindered the construction of CRAds that can selectively replicate in target tumor cells to achieve a useful therapeutic index for clinical utility. Lastly, absence of a non-invasive in vivo imaging method to detect CRAd replication and spread has hampered an understanding of CRAd biology in vivo. To achieve full therapeutic potential of CRAds for esophageal adenocarcinoma, we propose the construction of promoter-driven, infectivity-enhanced CRAds with imaging capabilities. To address the first issue, we have identified three promising promoters that exhibit favorable "tumor versus liver" and "tumor versus normal mucosa" differentials which are critical for utility in an adenoviral context. As well, we have developed methods to alter the tropism of adenoviruses, thereby achieving infectivity enhancement of tumor target ceils. The incorporation of an RGD4C motif in the HI loop of the fiber-knob region and Ad5/3 chimeric fiber modification has been shown to dramatically improve the infectious potency of adenovirus on esophageal adenocarcinoma cells. These findings offer solutions to the problem of esophageal adenocarcinoma cell resistance to adenoviral infection. In addition, we will configure optical and radiological imaging functions into our infectivity enhanced CRAds driven by optimal promoter. These features provide minimally invasive detection of CRAd replication and spread in a clinical setting, serving as a monitoring system with relevance to patient safety. Thus, it is obvious that infectivity-enhanced CRAds controlled by an optimal promoter element and possessing an imaging capability will be a therapeutic agent with great clinical utility for esophageal adenocarcinoma. The applicability of these modalities will be established from both toxicological and tumoricidal effect standpoints along with confirmation of CRAd functionality by optical and radiological imaging.