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Improved systemic antitumor therapy with oncolytic adenoviruses by replacing the fiber shaft HSG-binding domain with RGD

Gene Therapy volume 19, pages 453–457 (2012)Cite this article

Abstract

Retargeting oncolytic adenoviruses from their systemic preeminent liver tropism to disseminated tumor foci would highly improve the efficacy of these agents at eradicating tumors. We have replaced the KKTK fiber shaft heparan sulfate glycosaminoglycan-binding domain with an RGDK motif in order to achieve simultaneously liver detargeting and tumor targeting. When inserted into a wild-type backbone, this mutation palliated liver transaminase elevation and hematological alterations in mice. Importantly, when tested in a backbone that redirects E1A transcription towards pRB pathway deregulation, RGD at this novel shaft location also improved significantly systemic antitumor therapy compared with the broadly used RGD location at the HI-loop of the fiber knob domain.

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Acknowledgements

We thank Blanca Luena and Eduard Serra for their technical assistance. This work was supported by BIO2008-04692-C03-01 (RA) from the ‘Ministerio de Ciencia y Tecnología’ and FIS grant PI08/1661 (MC) from the Instituto de Salud Carlos III of the Government of Spain, 2009SGR283 research grant (RA) from the ‘Generalitat de Catalunya’, and by Mutua Madrileña Medical Research Foundation (MC). RA belongs to the Network of Cooperative Research on Cancer (C03-10), ‘Instituto de Salud Carlos III’ of the Government of Spain.

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  1. J J Rojas and M Gimenez-Alejandre: These authors contributed equally to this work.

Authors and Affiliations

  1. Translational Research Laboratory, IDIBELL-Institut Català d’Oncologia, L’Hospitalet de Llobregat, Barcelona, Spain

    J J Rojas, M Gimenez-Alejandre, R Gil-Hoyos, M Cascallo & R Alemany

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  1. J J Rojas
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  2. M Gimenez-Alejandre
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  3. R Gil-Hoyos
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  4. M Cascallo
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  5. R Alemany
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Correspondence to R Alemany.

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Rojas, J., Gimenez-Alejandre, M., Gil-Hoyos, R. et al. Improved systemic antitumor therapy with oncolytic adenoviruses by replacing the fiber shaft HSG-binding domain with RGD. Gene Ther 19, 453–457 (2012). https://doi.org/10.1038/gt.2011.106

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