Oncolytic adenoviruses (OAds) are promising agents for cancer therapy, representing a novel therapeutic strategy for pancreatic ductal adenocarcinoma (PDAC). However, there are challenges associated with the successful use of an OAd alone, involving the security of the viral vector and screening of an effective antitumor gene. In the present study, a novel OAd CD55-ST13-tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) was constructed in which the dual therapeutic genes ST13 and TRAIL were inserted, featuring the carcinoembryonic antigen (CEA) as a promoter to control E1A and deletion of the 55 kDa E1B gene. ST13, known as a colorectal cancer suppressor gene, exhibited lower expression in PDAC than in tumor-adjacent tissues and was associated with poor prognosis in PDAC patients. In vitro studies demonstrated that CD55-ST13-TRAIL was effective in promoting the expression of ST13 and TRAIL in CEA-positive pancreatic cancer cells. Moreover, CD55-ST13-TRAIL exhibited a synergistic effect toward tumor cell death compared with CD55-ST13 alone or CD55-TRAIL alone, and inhibited tumor cell proliferation and induced cell apoptosis dependent on caspase pathways in PDAC cells. Furthermore, xenograft experiments in a mouse model indicated that CD55-ST13-TRAIL significantly inhibited tumor growth and improved the survival of animals with xenografts. The findings demonstrate that oncolytic virotherapy under the control of the promoter CEA enables safe and efficient treatment of PDAC, and suggest that it represents a promising candidate for the treatment of metastatic diseases.

中文翻译：

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表达 ST13 的溶瘤腺病毒增加肿瘤坏死因子相关凋亡诱导配体对胰腺导管腺癌的抗肿瘤作用。

溶瘤腺病毒 (OAds) 是一种很有前景的癌症治疗药物，代表了胰腺导管腺癌 (PDAC) 的一种新治疗策略。然而，单独使用 OAd 存在挑战，包括病毒载体的安全性和有效抗肿瘤基因的筛选。本研究构建了一种新型 OAd CD55-ST13-肿瘤坏死因子相关凋亡诱导配体 (TRAIL)，其中插入了双重治疗基因 ST13 和 TRAIL，以癌胚抗原 (CEA) 作为启动子控制E1A 和 55 kDa E1B 基因的缺失。ST13 被称为结直肠癌抑制基因，在 PDAC 中的表达低于肿瘤邻近组织，并且与 PDAC 患者的不良预后相关。体外研究表明CD55-ST13-TRAIL可有效促进CEA阳性胰腺癌细胞中ST13和TRAIL的表达。此外，与单独的 CD55-ST13 或单独的 CD55-TRAIL 相比，CD55-ST13-TRAIL 对肿瘤细胞死亡具有协同作用，并抑制肿瘤细胞增殖并诱导 PDAC 细胞中依赖于半胱天冬酶途径的细胞凋亡。此外，小鼠模型中的异种移植实验表明，CD55-ST13-TRAIL 显着抑制了肿瘤生长并提高了异种移植动物的存活率。研究结果表明，在启动子 CEA 控制下的溶瘤病毒疗法能够安全有效地治疗 PDAC，并表明它代表了治疗转移性疾病的有希望的候选者。