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Significance Statement
Induction of cyclin E by adenoviral E1B55K protein is required for productive virus replication in normal cells. However this viral protein is not required in cancer cells, allowing E1B55K-deleted adenoviruses to conduct oncolytic replication (Fig. A). In many cancer cells cyclin E expression is already deregulated, likely because that the cellular factors targeted by E1B55K may already be activated or there are E1B55K-like factors to relax cyclin E regulation. As the cyclin E promoter is highly active in many types of cancer cells and is further stimulated after adenovirus infection, Cheng and colleagues first applied this unique property of cyclin E promoter into the design of a novel tumor-specific oncolytic adenoviral vector Ad-cycE, in which the cyclin E promoter was used to control the critical regulatory viral E1a gene. Significant and selective antitumor efficacy can be achieved with Ad-cycE (Fig. B). In this study, Cheng et al. further present an interesting new model for the study in an immunocompetent preclinical model of lung cancer. This new model could be of great value in the preclinical development of the new anticancer agents and allow researchers to better evaluate oncolytic adenoviral vectors in a more patient-like setting.
Journal Reference
Cheng PH1, Rao XM2, Wechman SL3,4, Li XF5, McMasters KM6,7, Zhou HS8,9,10.
[expand title=”Show Affiliations”]- Department of Pharmacology and Toxicology, University of Louisville School of Medicine, Louisville, KY, 40292, USA. [email protected].
- James Graham Brown Cancer Center, University of Louisville Medical School, 505 South Hancock Street, CTR Building, Room 306, Louisville, KY, 40202, USA. [email protected].
- Department of Pharmacology and Toxicology, University of Louisville School of Medicine, Louisville, KY, 40292, USA. [email protected].
- Hiram C. Polk Jr MD Department of Surgery, University of Louisville School of Medicine, Louisville, KY, 40292, USA. [email protected].
- Department of Diagnostic Radiology, University of Louisville School of Medicine, Louisville, KY, 40292, USA. [email protected].
- Department of Pharmacology and Toxicology, University of Louisville School of Medicine, Louisville, KY, 40292, USA. [email protected].
- Hiram C. Polk Jr MD Department of Surgery, University of Louisville School of Medicine, Louisville, KY, 40292, USA. [email protected].
- James Graham Brown Cancer Center, University of Louisville Medical School, 505 South Hancock Street, CTR Building, Room 306, Louisville, KY, 40202, USA. [email protected].
- Hiram C. Polk Jr MD Department of Surgery, University of Louisville School of Medicine, Louisville, KY, 40292, USA. [email protected].
- 0Department of Microbiology and Immunology, University of Louisville School of Medicine, Louisville, KY, 40292, USA. [email protected].[/expand]
Abstract
BACKGROUND:
Clinical trials have indicated that preclinical results obtained with human tumor xenografts in mouse models may overstate the potential of adenovirus (Ad)-mediated oncolytic therapies. We have previously demonstrated that the replication of human Ads depends on cyclin E dysregulation or overexpression in cancer cells. ED-1 cell derived from mouse lung adenocarcinomas triggered by transgenic overexpression of human cyclin E may be applied to investigate the antitumor efficacy of oncolytic Ads.
METHODS:
Ad-cycE was used to target cyclin E overexpression in ED-1 cells and repress tumor growth in a syngeneic mouse model for investigation of oncolytic virotherapies.
RESULTS:
Murine ED-1 cells were permissive for human Ad replication and Ad-cycE repressed ED-1 tumor growth in immunocompetent FVB mice. ED-1 cells destroyed by oncolytic Ads in tumors were encircled in capsule-like structures, while cells outside the capsules were not infected and survived the treatment.
CONCLUSION:
Ad-cycE can target cyclin E overexpression in cancer cells and repress tumor growth in syngeneic mouse models. The capsule structures formed after Ad intratumoral injection may prevent viral particles from spreading to the entire tumor.
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