Strong antitumor efficacy of a pancreatic tumor-targeting oncolytic adenovirus for neuroendocrine tumors.

Yuki Yamamoto,Marina Henmi,Yoshinori Ino,Kazunori Aoki,Masaki Nagasato,Masatoshi Tagawa,Nobuyoshi Hiraoka,Shinichi Yachida,Yosei Rin,Rieko Ohki

doi:10.1002/cam4.1185

Abstract

Although oncolytic adenoviruses are promising cancer therapy agents, for effective oncolytic activity, viruses need to specifically infect and effectively replicate in cancer cells but not in normal cells. We have previously identified a pancreatic cancer‐targeting ligand, SYENFSA (SYE), by screening an adenovirus library displaying random peptides against human pancreatic cancer cells and reported that a survivin promoter‐regulated adenovirus, displaying the SYE ligand (AdSur‐SYE), provided effective oncolysis of pancreatic ductal adenocarcinoma (PDAC) in a preclinical study. As we examined the infectivity of AdSur‐SYE in human surgical specimens of various pancreatic tumors, we unexpectedly found that AdSur‐SYE showed high gene transduction efficiency for pancreatic neuroendocrine tumors (PNETs) as well as for PDAC, 9.1‐ and 6.2‐fold, respectively, compared to that of the nontargeting virus (AdSur). The infectivity of both vectors was almost the same in other cancers and organs such as the pancreas. Immunostaining indicated that the cells infected with AdSur‐SYE were PNET cells but not stromal cells. AdSur‐SYE showed a significantly higher oncolytic potency than that of AdSur in human PNET cell lines, and intratumoral infection with AdSur‐SYE completely diminished subcutaneous tumors in a murine model, in which AdSur‐SYE effectively proliferated and spread. AdSur‐SYE exerted a stronger oncolytic effect in primary PNET cells cocultured with mouse embryonic fibroblasts than AdSur did. Thus, AdSur‐SYE shows promise as a next‐generation therapy for PNET.

Highlights

Oncolytic viruses, which are capable of replicating in cancer cells, have shown promising results in various cancer models
The surgical specimens of human pancreatic tumor were processed into sliced pieces (1~4 mm in diameter), and the virus solution was added in the culture medium containing small pieces of pancreatic neuroendocrine tumors (PNETs) tissues
These results showed that the targeting sequence SYE enhanced the gene transduction efficiency of the adenovirus vector for pancreatic ductal adenocarcinoma (PDAC) and for PNET

Summary

Introduction

Oncolytic viruses, which are capable of replicating in cancer cells, have shown promising results in various cancer models. Oncolytic adenoviruses based on human serotype 5 are one of the best-studied viruses, owing to their high-titer production and highly effective infection of a wide spectrum of dividing and nondividing cells both in vitro and in vivo. Two types of the adenovirus are used to restrict the viral replication to cancer cells, without affecting normal cells [4, 5]. The second type involves the construction of adenoviruses in which the transcription of E1 genes is restricted to cancer cells by tumor-or tissue-specific promoters such as the prostate-specific antigen, survivin, midkine, and telomerase reverse transcriptase promoters [4, 5].

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Conclusion