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The novel oncolytic adenoviral mutant Ad5-3Δ-A20T retargeted to αvβ6 integrins efficiently eliminates pancreatic cancer cells

Man, Y. K. Stella, Davies, James A., Coughlan, Lynda, Pantelidou, Constantia, Blázquez-Moreno, Alfonso, Marshall, John F., Parker, Alan L. and Halldén, Gunnel 2018. The novel oncolytic adenoviral mutant Ad5-3Δ-A20T retargeted to αvβ6 integrins efficiently eliminates pancreatic cancer cells. Molecular Cancer Therapeutics 17 (2) , pp. 575-587. 10.1158/1535-7163.MCT-17-0671

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Abstract

Metastatic pancreatic ductal adenocarcinomas (PDAC) are incurable due to the rapid development of resistance to all current therapeutics. Oncolytic adenoviral mutants have emerged as a promising new strategy that negates such resistance. In contrast to normal tissue, the majority of PDACs express the αvβ6 integrin receptor. To exploit this feature, we modified our previously reported oncolytic adenovirus, AdΔΔ, to selectively target αvβ6 integrins to facilitate systemic delivery. Structural modifications to AdΔΔ include the expression of the small but potent αvβ6-binding peptide, A20FMDV2, and ablation of binding to the native coxsackie and adenovirus receptor (CAR) within the fiber knob region. The resultant mutant, Ad5-3Δ-A20T, infected and killed αvβ6 integrin–expressing cells more effectively than the parental wild-type (Ad5wt) virus and AdΔΔ. Viral uptake through αvβ6 integrins rather than native viral receptors (CAR, αvβ3 and αvβ5 integrins) promoted viral propagation and spread. Superior efficacy of Ad5-3Δ-A20T compared with Ad5wt was demonstrated in 3D organotypic cocultures, and similar potency between the two viruses was observed in Suit-2 in vivo models. Importantly, Ad5-3Δ-A20T infected pancreatic stellate cells at low levels, which may further facilitate viral spread and cancer cell elimination either as a single agent or in combination with the chemotherapy drug, gemcitabine. We demonstrate that Ad5-3Δ-A20T is highly selective for αvβ6 integrin–expressing pancreatic cancer cells, and with further development, this new and exciting strategy can potentially be extended to improve the systemic delivery of adenoviruses to pancreatic cancer patients.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Medicine
Publisher: American Association for Cancer Research
ISSN: 1535-7163
Date of First Compliant Deposit: 29 January 2018
Date of Acceptance: 17 January 2018
Last Modified: 28 May 2019 23:59
URI: http://orca.cf.ac.uk/id/eprint/108568

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