A novel conditionally replicating "armed" adenovirus selectively targeting gastrointestinal tumors with aberrant wnt
Xinjian Liu1, Qijun Qian, Ping Xu
1State Key Laboratory of Oncogenes and Related Genes, Cancer Institute, Shanghai Jiaotong University, Shanghai, China.
Abstract:
Using conditionally replicating adenoviral vectors (CRAds) is a promising strategy in the treatment of solid tumors. The prospective of this study was to design a novel CRAd for the treatment of gastrointestinal cancer and show its efficacy in vitro, as well as in vivo. To determine if aberrant wnt signaling in tumor cells can be used to selectively drive viral replication, we analyzed six colorectal and hepatocellular cell lines, as well as 13 colorectal tumors and 17 gastric tumors, for β-catenin mutation status or aberrant wnt signaling, both of which were found frequently. Based on these findings, a novel CRAd (Ad5F11.wnt-E1A-hIL24) containing an E1A expression cassette driven by an artificial wnt promoter and delivering an apoptosis-inducing gene, interleukin-24 (IL24), was engineered. To enhance infection efficiency, the virus was pseudotyped by replacing adenovirus serotype 5 (Ad5) with Ad11 fiber. Ad5F11.wnt-E1A-hIL24 virus exhibited high selectivity toward cells with aberrant wnt signaling both in vitro and in mouse xenograft tumors. Transduction efficiency was significantly improved compared with that of nonpseudotyped control viruses. The proliferation of tumor cell lines, as well as tumor growth, in mouse xenografts could be profoundly inhibited by viral infection with Ad5F11.wnt-E1A-hIL24. The therapeutic effect was associated with increased apoptosis through caspase-3 activation. In addition, Ad5F11b vector exhibited a more favorable biodistribution, blood clearance, and transgene expression compared with conventional Ad5 vector after systemic or intratumoral injection in human gastrointestinal cancer xenografts. We think that our approach is a promising strategy in the treatment of gastrointestinal cancer, warranting further clinical investigation.
Insights
A novel conditionally replicating adenoviral vector (CRAd) targets gastrointestinal cancers by exploiting aberrant Wnt signaling. This engineered virus, Ad5F11.wnt-E1A-hIL24, selectively replicates in tumors, inhibits growth, and induces apoptosis, showing promise for cancer therapy.
Area of Science:
- Oncolytic virotherapy
- Gene therapy
- Gastrointestinal oncology
Background:
- Conditionally replicating adenoviral vectors (CRAds) show potential for solid tumor treatment.
- Aberrant Wnt signaling is frequently observed in colorectal and gastric cancers, presenting a therapeutic target.
Purpose of the Study:
- To design and evaluate a novel CRAd for gastrointestinal cancer treatment.
- To leverage aberrant Wnt signaling for selective viral replication and enhanced therapeutic efficacy.
Main Methods:
- Engineered a novel CRAd (Ad5F11.wnt-E1A-hIL24) with a Wnt-inducible E1A promoter and IL24 gene.
- Pseudotyped the adenovirus with Ad11 fiber to improve transduction efficiency.
- Assessed viral selectivity, replication, and anti-tumor activity in vitro and in vivo (mouse xenografts).
Main Results:
- Ad5F11.wnt-E1A-hIL24 demonstrated high selectivity for Wnt-aberrant cells, both in vitro and in vivo.
- Viral infection significantly inhibited tumor cell proliferation and xenograft tumor growth, inducing apoptosis via caspase-3 activation.
- The Ad5F11b vector showed improved biodistribution and clearance compared to Ad5 vectors.
Conclusions:
- The engineered CRAd, Ad5F11.wnt-E1A-hIL24, is a promising therapeutic strategy for gastrointestinal cancers.
- Targeting aberrant Wnt signaling offers a selective approach for oncolytic virotherapy.
- Further clinical investigation of this Wnt-targeted CRAd is warranted.
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