The αvβ6 integrin specific virotherapy, Ad5NULL-A20.FCU1, selectively delivers 2 potent “in-tumour” chemotherapy to Pancreatic Ductal Adenocarcinoma

Badder, Luned, Davies, James ORCID: https://orcid.org/0000-0003-3569-4500, Meniel, Valerie, Maruskova, Mahulena, Salvador, Beatriz, Bayliss, Rebecca ORCID: https://orcid.org/0000-0002-3324-957X, Phesse, Toby ORCID: https://orcid.org/0000-0001-9568-4916, Hogan, Catherine ORCID: https://orcid.org/0000-0002-1012-0896 and Parker, Alan ORCID: https://orcid.org/0000-0002-9302-1761 2024. The αvβ6 integrin specific virotherapy, Ad5NULL-A20.FCU1, selectively delivers 2 potent “in-tumour” chemotherapy to Pancreatic Ductal Adenocarcinoma. British Journal of Cancer 10.1038/s41416-024-02869-3

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Abstract

Background Pancreatic ductal adenocarcinoma (PDAC) represent an unmet clinical need. Approximately 90% of PDACs express high levels of αvβ6 integrin. We have previously described Ad5NULL-A20, an adenovirus vector with ablated native means of cell entry and retargeted to αvβ6 integrin by incorporation of an A20 peptide. Methods Here, we incorporate suicide genes FCY1 and FCU1 encoding for cytosine deaminase (CDase) or a combination of CDase and UPRTase, capable of catalysing a non-toxic prodrug, 5-FC into the chemotherapeutic 5-FU and downstream metabolites, into replication-deficient Ad5 and Ad5NULL-A20. Results We show that Ad5NULL-A20 enables the transfer of suicide genes to αvβ6 integrin-positive PDAC cells which, in combination with 5-FC, results in cell death in vitro which is further mediated by a bystander effect in non-transduced cells. Intratumoural delivery of Ad5NULL-A20.FCU1 in combination with intraperitoneal delivery of 5-FC further results in tumour growth inhibition in a cell line xenograft in vivo. Using clinically-relevant 3D organoid models, we show selective transduction and therapeutic efficacy of FCU1 transgenes in combination with 5-FC. Conclusion Taken together these data provide the preclinical rationale for combined Ad5NULL-A20.FCU1 plus 5-FC as a promising targeted therapy to mediate “in-tumour chemotherapy” and merits further investigation for the treatment of PDAC patients.

Item Type:	Article
Date Type:	Published Online
Status:	In Press
Schools:	Medicine Biosciences European Cancer Stem Cell Research Institute (ECSCRI) Systems Immunity Research Institute (SIURI)
Publisher:	Springer Nature
ISSN:	0007-0920
Date of First Compliant Deposit:	15 October 2024
Date of Acceptance:	25 September 2024
Last Modified:	15 Oct 2024 11:15
URI:	https://orca.cardiff.ac.uk/id/eprint/172424

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