{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,25]],"date-time":"2026-09-25T14:31:23Z","timestamp":1790346683891,"version":"4.1.0"},"reference-count":60,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2024,1,19]],"date-time":"2024-01-19T00:00:00Z","timestamp":1705622400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"UK charity Pancreatic Cancer Research Fund (PCRF)","award":["C16420\/A18066"],"award-info":[{"award-number":["C16420\/A18066"]}]},{"name":"BCI CRUK Centre Grant","award":["C16420\/A18066"],"award-info":[{"award-number":["C16420\/A18066"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Pancreatic ductal adenocarcinoma (PDAC) is the most aggressive type of pancreatic cancer, which rapidly develops resistance to the current standard of care. Several oncolytic Human AdenoViruses (HAdVs) have been reported to re-sensitize drug-resistant cancer cells and in combination with chemotherapeutics attenuate solid tumour growth. Obstacles preventing greater clinical success are rapid hepatic elimination and limited viral replication and spread within the tumour microenvironment. We hypothesised that higher intratumoural levels of the virus could be achieved by altering cellular epigenetic regulation. Here we report on the screening of an enriched epigenetics small molecule library and validation of six compounds that increased viral gene expression and replication. The greatest effects were observed with three epigenetic inhibitors targeting bromodomain (BRD)-containing proteins. Specifically, BRD4 inhibitors enhanced the efficacy of Ad5 wild type, Ad\u2206\u2206, and Ad-3\u2206-A20T in 3-dimensional co-culture models of PDAC and in vivo xenografts. RNAseq analysis demonstrated that the inhibitors increased viral E1A expression, altered expression of cell cycle regulators and inflammatory factors, and attenuated expression levels of tumour cell oncogenes such as c-Myc and Myb. The data suggest that the tumour-selective Ad\u2206\u2206 and Ad-3\u2206-A20T combined with epigenetic inhibitors is a novel strategy for the treatment of PDAC by eliminating both cancer and associated stromal cells to pave the way for immune cell access even after systemic delivery of the virus.<\/jats:p>","DOI":"10.3390\/ijms25021265","type":"journal-article","created":{"date-parts":[[2024,1,19]],"date-time":"2024-01-19T11:04:57Z","timestamp":1705662297000},"page":"1265","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Inhibition of Bromodomain Proteins Enhances Oncolytic HAdVC5 Replication and Efficacy in Pancreatic Ductal Adenocarcinoma (PDAC) Models"],"prefix":"10.3390","volume":"25","author":[{"given":"Tizong","family":"Miao","sequence":"first","affiliation":[{"name":"Centre for Biomarkers and Biotherapeutics, Barts Cancer Institute, Queen Mary University of London, London EC1M 6BQ, UK"},{"name":"Centre for Immunobiology, Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London E1 2AT, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alistair","family":"Symonds","sequence":"additional","affiliation":[{"name":"Centre for Immunobiology, Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London E1 2AT, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Oliver J.","family":"Hickman","sequence":"additional","affiliation":[{"name":"Cancer Drug Target Discovery Laboratory, The Institute of Cancer Research, London SW3 6JB, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dongsheng","family":"Wu","sequence":"additional","affiliation":[{"name":"Bioimaging Centre, School of Engineering and Materials Science, Queen Mary University of London, London E1 4NS, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ping","family":"Wang","sequence":"additional","affiliation":[{"name":"Centre for Immunobiology, Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London E1 2AT, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nick","family":"Lemoine","sequence":"additional","affiliation":[{"name":"Centre for Biomarkers and Biotherapeutics, Barts Cancer Institute, Queen Mary University of London, London EC1M 6BQ, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2367-6313","authenticated-orcid":false,"given":"Yaohe","family":"Wang","sequence":"additional","affiliation":[{"name":"Centre for Biomarkers and Biotherapeutics, Barts Cancer Institute, Queen Mary University of London, London EC1M 6BQ, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Spiros","family":"Linardopoulos","sequence":"additional","affiliation":[{"name":"Cancer Drug Target Discovery Laboratory, The Institute of Cancer Research, London SW3 6JB, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5680-2895","authenticated-orcid":false,"given":"Gunnel","family":"Halld\u00e9n","sequence":"additional","affiliation":[{"name":"Centre for Biomarkers and Biotherapeutics, Barts Cancer Institute, Queen Mary University of London, London EC1M 6BQ, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,1,19]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"17","DOI":"10.3322\/caac.21763","article-title":"Cancer statistics, 2023","volume":"73","author":"Siegel","year":"2023","journal-title":"CA Cancer J. 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