Holbrook Molly C, Goad Dakota W, Grdzelishvili Valery Z
Department of Biological Sciences, University of North Carolina at Charlotte, Charlotte, NC 28223, USA.
Cancers (Basel). 2021 Mar 9;13(5):1171. doi: 10.3390/cancers13051171.
Pancreatic ductal adenocarcinoma (PDAC) is a devastating malignancy with poor prognosis and a dismal survival rate, expected to become the second leading cause of cancer-related deaths in the United States. Oncolytic virus (OV) is an anticancer approach that utilizes replication-competent viruses to preferentially infect and kill tumor cells. Vesicular stomatitis virus (VSV), one such OV, is already in several phase I clinical trials against different malignancies. VSV-based recombinant viruses are effective OVs against a majority of tested PDAC cell lines. However, some PDAC cell lines are resistant to VSV. Upregulated type I IFN signaling and constitutive expression of a subset of interferon-simulated genes (ISGs) play a major role in such resistance, while other mechanisms, such as inefficient viral attachment and resistance to VSV-mediated apoptosis, also play a role in some PDACs. Several alternative approaches have been shown to break the resistance of PDACs to VSV without compromising VSV oncoselectivity, including (i) combinations of VSV with JAK1/2 inhibitors (such as ruxolitinib); (ii) triple combinations of VSV with ruxolitinib and polycations improving both VSV replication and attachment; (iii) combinations of VSV with chemotherapeutic drugs (such as paclitaxel) arresting cells in the G2/M phase; (iv) arming VSV with p53 transgenes; (v) directed evolution approach producing more effective OVs. The latter study demonstrated impressive long-term genomic stability of complex VSV recombinants encoding large transgenes, supporting further clinical development of VSV as safe therapeutics for PDAC.
胰腺导管腺癌（PDAC）是一种预后不良、生存率极低的毁灭性恶性肿瘤，预计将成为美国癌症相关死亡的第二大主要原因。溶瘤病毒（OV）是一种抗癌方法，它利用具有复制能力的病毒优先感染并杀死肿瘤细胞。水泡性口炎病毒（VSV）就是这样一种溶瘤病毒，已进入针对不同恶性肿瘤的多项I期临床试验。基于VSV的重组病毒对大多数测试的PDAC细胞系都是有效的溶瘤病毒。然而，一些PDAC细胞系对VSV具有抗性。I型干扰素信号上调和一部分干扰素刺激基因（ISG）的组成性表达在这种抗性中起主要作用，而其他机制，如病毒附着效率低下和对VSV介导的凋亡的抗性，在一些PDAC中也起作用。已经证明了几种替代方法可以打破PDAC对VSV的抗性，同时不影响VSV的肿瘤选择性，包括：（i）VSV与JAK1/2抑制剂（如鲁索替尼）联合使用；（ii）VSV与鲁索替尼和聚阳离子的三联组合，可提高VSV的复制和附着能力；（iii）VSV与化疗药物（如紫杉醇）联合使用，使细胞停滞在G2/M期；（iv）用p53转基因武装VSV；（v）定向进化方法生产更有效的溶瘤病毒。后一项研究证明了编码大转基因的复杂VSV重组体具有令人印象深刻的长期基因组稳定性，支持将VSV作为PDAC的安全治疗方法进行进一步的临床开发。
