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dc.contributor.authorEdge, S.D.
dc.contributor.authorRenard, I.
dc.contributor.authorPyne, E.
dc.contributor.authorMoody, Hannah
dc.contributor.authorRoy, R.
dc.contributor.authorBeavis, A.W.
dc.contributor.authorArchibald, S.J.
dc.contributor.authorCawthorne, C.J.
dc.contributor.authorMaher, S.G.
dc.contributor.authorPires, I.M.
dc.date.accessioned2021-02-15T16:10:18Z
dc.date.accessioned2021-02-19T14:22:18Z
dc.date.available2021-02-15T16:10:18Z
dc.date.available2021-02-19T14:22:18Z
dc.date.issued2021-01
dc.identifier.citationEdge SD, Renard I, Pyne E et al (2021) PI3K inhibition as a novel therapeutic strategy for neoadjuvant chemoradiotherapy resistant oesophageal adenocarcinoma. British Journal of Radiology. 94(1119)en_US
dc.identifier.urihttp://hdl.handle.net/10454/18357
dc.descriptionNoen_US
dc.description.abstractNeoadjuvant chemoradiotherapy (neo-CRT) prior to surgery is the standard of care for oesophageal adenocarcinoma (OAC) patients. Unfortunately, most patients fail to respond to treatment. MiR-187 was previously shown to be downregulated in neo-CRT non-responders, whist in vitro miR-187 overexpression enhanced radiosensitivity and upregulated PTEN. This study evaluates the role of miR-187 and downstream PI3K signalling in radiation response in OAC. The effect of miR-187 overexpression on downstream PI3K signalling was evaluated in OAC cell lines by qPCR and Western blotting. PTEN expression was analysed in OAC pre-treatment biopsies of neo-CRT responders and non-responders. Pharmacological inhibition of PI3K using GDC-0941 was evaluated in combination with radiotherapy in two-dimensional and three-dimensional OAC models in vitro and as a single agent in vivo. Radiation response in vitro was assessed via clonogenic assay. PTEN expression was significantly decreased in neo-CRT non-responders. MiR-187 overexpression significantly upregulated PTEN expression and inhibited downstream PI3K signalling in vitro. GDC-0941 significantly reduced viability and enhanced radiation response in vitro and led to tumour growth inhibition as a single agent in vivo. Targeting of PI3K signalling is a promising therapeutic strategy for OAC patients who have repressed miR-187 expression and do not respond to conventional neo-CRT. This is the first study evaluating the effect of PI3K inhibition on radiosensitivity in OAC, with a particular focus on patients that do not respond to neo-CRT. We have shown for the first time that targeting of PI3K signalling is a promising alternative therapeutic strategy for OAC patients who do not respond to conventional neo-CRT.en_US
dc.language.isoenen_US
dc.relation.isreferencedbyhttps://doi.org/10.1259/bjr.20201191en_US
dc.subjectOesophageal adenocarcinomaen_US
dc.subjectPI3K inhibitionen_US
dc.subjectNeoadjuvant chemoradiotherapyen_US
dc.titlePI3K inhibition as a novel therapeutic strategy for neoadjuvant chemoradiotherapy resistant oesophageal adenocarcinomaen_US
dc.status.refereedYesen_US
dc.date.Accepted2020-12-22
dc.date.application2021-01-12
dc.typeArticleen_US
dc.type.versionNo full-text in the repositoryen_US
dc.date.updated2021-02-15T16:10:19Z
dc.openaccess.statusNot Open Accessen_US


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