Enhanced CRAd for Esophageal Adenocarcinoma

描述(由申请人提供)： 食管腺癌现在是西方男性增长最快的癌症类别。此外，尽管目前的治疗取得了进展，但局部晚期疾病的预后仍然停滞不前。这些事实清楚地表明了开发新的食管腺癌治疗方法的必要性。尽管条件复制型腺病毒(CRAds)为接近胃肠道实体瘤提供了一种新的有效方法，但由于腺病毒主要受体(柯萨奇-腺病毒受体，CAR)的极低表达，食管腺癌细胞对腺病毒感染具有极强的抵抗力。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，使其能够选择性地在靶肿瘤细胞中复制，从而达到临床实用的治疗指标。最后，缺少一个 非侵入性的体内成像方法检测CRAd的复制和扩散阻碍了对CRAd体内生物学的了解。为了充分发挥CRAds对食管腺癌的治疗潜力，我们建议构建启动子驱动的、感染性增强的具有成像能力的CRAds。为了解决第一个问题，我们已经确定了三个有希望的启动子，它们表现出良好的“肿瘤与肝脏”和“肿瘤与正常黏膜”的区别，这对于腺病毒背景下的实用至关重要。此外，我们还开发了改变腺病毒的趋向性的方法，从而实现了肿瘤靶细胞的感染性增强。将RGD4C基序掺入纤维结节区域的HI环和Ad5/3嵌合纤维修饰已被证明显著提高了腺病毒对食管腺癌细胞的感染能力。这些发现为食管腺癌细胞对腺病毒感染的抵抗力问题提供了解决方案。此外，我们将在由最佳启动子驱动的传染性增强型CRAD中配置光学和放射成像功能。这些功能在临床环境中提供CRAd复制和传播的微创检测，作为与患者安全相关的监测系统。由此可见，由最佳启动子元件调控的、具有显影能力的感染性增强型CRAD将是一种具有较大临床应用价值的食管腺癌治疗剂。这些模式的适用性将从毒理学和杀瘤效应的角度进行确定，同时通过光学和放射成像确认CRAd的功能。

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.