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Enhanced CRAd for Esophageal Adenocarcinoma

增强型 CRAd 治疗食管腺癌

基本信息

批准号：
7239609
负责人：
MASATO YAMAMOTO
金额：
$ 32.88万
依托单位：
UNIVERSITY OF MINNESOTA
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 2009-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7239609
关键词：
Address Adenocarcinoma Cell Adenoviruses Animal Model Barrett Esophagus Biology Blood Vessels CAR receptor Categories Cell Culture System Clinical Clinical Trials Detection Development Disease Elements End Point Epithelial Esophageal Adenocarcinoma Exhibits Facility Construction Funding Category Fiber Gastrointestinal tract structure Glycoproteins Growth Factor Head and Neck Squamous Cell Carcinoma Human Image Imagery In Situ Incidence Infection Injection of therapeutic agent Invasive Lead Liver Liver neoplasms Malignant Neoplasms Methods Modality Modification Monitor Mucous Membrane Numbers Optics Outcome Population Primary Cell Cultures Proteins Reflux Resistance Safety Solid Neoplasm Solutions Specificity System Therapeutic Therapeutic Agents Therapeutic Effect Therapeutic Index Translations Tropism Viral base conditionally replicative adenovirus cyclooxygenase 2 gene therapy improved in vivo innovation men neoplastic neoplastic cell novel novel strategies novel therapeutics optical imaging outcome forecast patient safety promoter receptor somatostatin receptor 2 tumor

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）：