Adenovirus 11: a potential oncolytic virus for pancreatic cancer therapy?
Year: 2008
Session type: Poster / e-Poster / Silent Theatre session
Centre for Molecular Oncology and Imaging, Institute of Cancer, Barts and The London School of Medicine and Dentistry, Queen Mary, University of London, London, UK
Abstract
Background
Pancreatic cancer remains one of the most difficult cancers to treat. Clearly there is a need for the development of novel therapeutic strategies, such as oncolytic viruses. The first-generation oncolytic adenovirus, based on serotype 5 (Ad5), has shown disappointing results in pancreatic cancer trials. It is well-known that Ad5’s attachment receptor, named CAR, is often down-regulated in cancer cells. There is also a high prevalence of Ad5 neutralising antibodies in the normal population. In contrast a separate species of adenovirus, Ad11 binds to CD46 and has low prevalence of antibodies, but its potential as an oncolytic virus remains to be explored.
Method and results
Eight pancreatic cancer cell lines were screened by flow cytometry and all expressed significantly higher levels of CD46 compared to CAR. Half of these cell lines were resistant to Ad5 replication and oncolysis but were more sensitive to Ad11, and vice versa. There was no correlation between receptor expression and oncolytic potency. Viral attachment and nuclear localisation, as measured by quantitative PCR, were significantly better for Ad11 even in cells that were resistant to its killing. In these cells however, the amount of mRNA for Ad11’s E1A gene was greatly reduced, producing a down-stream effect on viral replication and cell lysis. In vivo data comparing Ad5 and Ad11 will be presented.
Conclusion
Our studies highlight the impressive infectivity of Ad11 and its potential for the treatment of pancreatic cancer. Identification of events that affect E1A transcription could lead to the improvement of adenoviral oncolytic therapy.
Background
Pancreatic cancer remains one of the most difficult cancers to treat. Clearly there is a need for the development of novel therapeutic strategies, such as oncolytic viruses. The first-generation oncolytic adenovirus, based on serotype 5 (Ad5), has shown disappointing results in pancreatic cancer trials. It is well-known that Ad5’s attachment receptor, named CAR, is often down-regulated in cancer cells. There is also a high prevalence of Ad5 neutralising antibodies in the normal population. In contrast a separate species of adenovirus, Ad11 binds to CD46 and has low prevalence of antibodies, but its potential as an oncolytic virus remains to be explored.
Method and results
Eight pancreatic cancer cell lines were screened by flow cytometry and all expressed significantly higher levels of CD46 compared to CAR. Half of these cell lines were resistant to Ad5 replication and oncolysis but were more sensitive to Ad11, and vice versa. There was no correlation between receptor expression and oncolytic potency. Viral attachment and nuclear localisation, as measured by quantitative PCR, were significantly better for Ad11 even in cells that were resistant to its killing. In these cells however, the amount of mRNA for Ad11’s E1A gene was greatly reduced, producing a down-stream effect on viral replication and cell lysis. In vivo data comparing Ad5 and Ad11 will be presented.
Conclusion
Our studies highlight the impressive infectivity of Ad11 and its potential for the treatment of pancreatic cancer. Identification of events that affect E1A transcription could lead to the improvement of adenoviral oncolytic therapy.
