Enhanced CRAd for Esophageal Adenocarcinoma

增强型 CRAd 治疗食管腺癌

基本信息

批准号：
7072246
负责人：
MASATO YAMAMOTO
金额：
$ 5.87万
依托单位：
UNIVERSITY OF ALABAMA AT BIRMINGHAM
依托单位国家：
美国
项目类别：
财政年份：
2003
资助国家：
美国
起止时间：
2003-08-01 至 2006-10-31
项目状态：
已结题

项目摘要

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.

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，尽管当前的管理进展，局部晚期疾病的预后仍然是静止的。这些事实清楚地表明了为食管腺癌开发新的治疗方法的必要性。即使有条件地复制腺病毒（Crads）提供了一种新型且有效的方式来接近胃肠道的实体瘤，但由于腺病毒原发性受体的最小表达，食管腺癌细胞对腺病毒感染具有极大的抗性（Coxsackie-Adeenovirus受体，Coxsackie-Adeenovirus受体，Car）。此外，缺乏对食管腺癌选择性的启动子，阻碍了可以在靶肿瘤细胞中选择性复制的CRAD的构建，以实现有用的治疗指数来实现临床实用性。最后，没有无创的体内成像方法检测CRAD复制和扩散已经阻碍了对体内Crad Biology的了解。为了获得食管腺癌的全部治疗潜力，我们提出了具有成像能力的启动子驱动的，感染性增强的Crads的构建。为了解决第一个问题，我们已经确定了三个有前途的启动子，它们表现出有利的“肿瘤与肝脏”和“肿瘤与正常粘膜”差异，这对于在腺病毒背景下对效用至关重要。同样，我们开发了改变腺病毒的最潮流的方法，从而实现了肿瘤靶CEIL的感染性增强。已证明，将RGD4C基序掺入纤维旋钮区域的HI环和AD5/3嵌合纤维修饰中，已显示可显着提高腺病毒对食管腺癌细胞上的传染性效力。这些发现为食管腺癌细胞对腺病毒感染的耐药性提供了解决方案。此外，我们将将光学和放射学成像功能配置为我们的感染性增强了由最佳启动子驱动的CRAD。这些功能可在临床环境中微创检测CRAD复制并扩散，并作为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控制的感染性增强的crads将是一种治疗剂，具有对食管腺癌的临床实用性。这些模式的适用性将从毒理学和肿瘤效应的角度以及通过光学和放射学成像确认CRAD功能。