Retargeted adenoviral cancer gene therapy for tumour cells overexpressing epidermal growth factor receptor or urokinase-type plasminogen activator receptor

Harvey, T. J., Burdon, D., Steele, L., Ingram, N., Hall, G. D., Selby, P. J., Vile, R. G., Cooper, P. A., Shnyder S. D. and Chester, J. D. (2010) Retargeted adenoviral cancer gene therapy for tumour cells overexpressing epidermal growth factor receptor or urokinase-type plasminogen activator receptor. Gene Therapy, 17 8: 1000-1010. doi:10.1038/gt.2010.45


Author Harvey, T. J.
Burdon, D.
Steele, L.
Ingram, N.
Hall, G. D.
Selby, P. J.
Vile, R. G.
Cooper, P. A.
Shnyder S. D.
Chester, J. D.
Title Retargeted adenoviral cancer gene therapy for tumour cells overexpressing epidermal growth factor receptor or urokinase-type plasminogen activator receptor
Journal name Gene Therapy   Check publisher's open access policy
ISSN 0969-7128
1476-5462
Publication date 2010
Sub-type Article (original research)
DOI 10.1038/gt.2010.45
Open Access Status Not Open Access
Volume 17
Issue 8
Start page 1000
End page 1010
Total pages 11
Place of publication London, United Kingdom
Publisher Nature Publishing Group
Language eng
Formatted abstract
We have assessed the ability of bispecific fusion proteins to improve adenovirus-mediated transfer of therapeutic and marker transgenes. We constructed an expression vector that can be easily modified to synthesize a variety of fusion proteins for retargeting adenoviral gene therapy vectors to cell surface markers, which are differentially expressed between normal and cancer cells. Adenoviral transduction can be improved in a number of tumour cell lines which overexpress EGFR (epidermal growth factor receptor) or uPAR (urokinase-type plasminogen activator receptor), but which have only low levels of endogenous hCAR (human coxsackie B and adenovirus receptor) expression. Up to 40-fold improvement in Β-galactosidase transgene expression was seen using an EGFR retargeting protein, and up to 16-fold using a second fusion protein targeting uPAR. In vitro, our uPAR retargeting fusion protein improved the sensitivity to adenoviral herpes simplex virus thymidine kinase/ganciclovir by an order of magnitude, whereas in vivo, our EGFR retargeting protein is able to significantly delay tumour growth in rodent animal models in a dose-dependent manner. The cassette design of our fusion protein constructs offers a flexible method for the straightforward synthesis of multiple adenoviral retargeting proteins, directed against a variety of tumour-associated antigens, for use in clinical trials.
Keyword Adenovirus
hCAR
Retargeting
Bladder cancer
EGFR
uPAR
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status Unknown

Document type: Journal Article
Sub-type: Article (original research)
Collection: School of Biomedical Sciences Publications
 
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Citation counts: TR Web of Science Citation Count  Cited 11 times in Thomson Reuters Web of Science Article | Citations
Scopus Citation Count Cited 10 times in Scopus Article | Citations
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Created: Wed, 20 Apr 2016, 16:25:47 EST by Elisha Bignell on behalf of School of Biomedical Sciences