A novel chromogranin-A promoter-driven oncolytic adenovirus for midgut carcinoid therapy
Justyna Leja1, Helena Dzojic, Elisabet Gustafson
1Division of Clinical Immunology, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden.
Purpose:
The use of replication-selective oncolytic adenoviruses is an emerging therapeutic approach for cancer, which thus far has not been employed for carcinoids. We therefore constructed Ad[CgA-E1A], a novel replication-selective oncolytic adenovirus, where the chromogranin A (CgA) promoter controls expression of the adenoviral E1A gene.
Experimental Design:
The Ad[CgA-E1A] virus was evaluated for E1A protein expression, replication ability, and cytolytic activity in various cell lines. It was also evaluated for treatment of xenografted human carcinoid tumors in nude mice. To use Ad[CgA-E1A] for the treatment of carcinoid liver metastases, it is important that normal hepatocytes do not support virus replication to minimize hepatotoxicity. We therefore evaluated CgA protein expression in normal hepatocytes. We also evaluated CgA gene expression in normal hepatocytes and microdissected tumor cells from carcinoid metastases.
Results:
We found that Ad[CgA-E1A] replicates similarly to wild-type virus in tumor cells with neuroendocrine features, including the BON carcinoid cell line and the SH-SY-5Y neuroblastoma cell lines, whereas it is attenuated in other cell types. Thus, cells where the CgA promoter is active are selectively killed. We also found that Ad[CgA-E1A] is able to suppress fast-growing human BON carcinoid tumors in nude mice. Furthermore, CgA is highly expressed in microdissected cells from carcinoid metastases, whereas it is not expressed in normal hepatocytes.
Conclusion:
Ad[CgA-E1A] is an interesting agent for the treatment of carcinoid liver metastases in conjunction with standard therapy for these malignancies.
Insights
A novel oncolytic adenovirus, Ad[CgA-E1A], selectively targets and kills carcinoid tumor cells by utilizing the chromogranin A promoter. This agent shows promise in suppressing carcinoid tumors in mice with minimal toxicity to normal cells.
Area of Science:
- Oncolytic virotherapy
- Gene therapy for cancer
- Adenovirus vector development
Background:
- Replication-selective oncolytic adenoviruses represent a promising cancer treatment strategy.
- Carcinoid tumors have not yet been targeted by oncolytic adenoviruses.
- Development of targeted oncolytic adenoviruses is crucial for expanding cancer therapy options.
Purpose of the Study:
- To construct and evaluate a novel replication-selective oncolytic adenovirus, Ad[CgA-E1A], for carcinoid tumor treatment.
- To engineer the adenovirus with the chromogranin A (CgA) promoter controlling E1A gene expression for tumor-specific replication.
- To assess the potential of Ad[CgA-E1A] in targeting carcinoid malignancies.
Main Methods:
- Ad[CgA-E1A] was tested for E1A protein expression, replication, and cytolytic activity in various cell lines.
- Tumor suppression was evaluated in nude mice bearing xenografted human carcinoid tumors.
- Chromogranin A (CgA) expression was analyzed in normal hepatocytes and microdissected carcinoid tumor cells to assess target specificity and potential hepatotoxicity.
Main Results:
- Ad[CgA-E1A] demonstrated selective replication and cytolytic activity in tumor cells with neuroendocrine features, including carcinoid and neuroblastoma cell lines.
- The virus significantly suppressed the growth of human carcinoid tumors in a mouse model.
- High CgA expression was observed in carcinoid metastases, while normal hepatocytes showed minimal to no expression, indicating tumor-specific targeting and reduced hepatotoxicity.
Conclusions:
- Ad[CgA-E1A] shows significant potential as an oncolytic agent for treating carcinoid liver metastases.
- The tumor-specific replication driven by the CgA promoter minimizes toxicity to healthy liver cells.
- Ad[CgA-E1A] could be a valuable addition to standard therapies for carcinoid malignancies.
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