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Evaluation of the dual mTOR/PI3K inhibitors Gedatolisib (PF-05212384) and PF-04691502 against ovarian cancer xenograft models
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dc.contributor.author | Langdon, Simon P. | |
dc.contributor.author | Kay, Charlene | |
dc.contributor.author | Um, In Hwa | |
dc.contributor.author | Muir, Morwenna | |
dc.contributor.author | Sellar, Grant | |
dc.contributor.author | Kan, Julie | |
dc.contributor.author | Gourley, Charlie | |
dc.contributor.author | Harrison, David James | |
dc.date.accessioned | 2019-12-11T14:30:01Z | |
dc.date.available | 2019-12-11T14:30:01Z | |
dc.date.issued | 2019-12-10 | |
dc.identifier | 264237069 | |
dc.identifier | fb167ed1-3576-42fd-96e1-04dafca41e17 | |
dc.identifier | 85076410311 | |
dc.identifier | 000501987600001 | |
dc.identifier.citation | Langdon , S P , Kay , C , Um , I H , Muir , M , Sellar , G , Kan , J , Gourley , C & Harrison , D J 2019 , ' Evaluation of the dual mTOR/PI3K inhibitors Gedatolisib (PF-05212384) and PF-04691502 against ovarian cancer xenograft models ' , Scientific Reports , vol. 9 , 18742 . https://doi.org/10.1038/s41598-019-55096-9 | en |
dc.identifier.issn | 2045-2322 | |
dc.identifier.other | ORCID: /0000-0001-9041-9988/work/66070020 | |
dc.identifier.other | ORCID: /0000-0001-9999-4292/work/158122918 | |
dc.identifier.uri | https://hdl.handle.net/10023/19120 | |
dc.description | We are grateful to Wyeth/Pfizer (ONC-EU-150) and to the Scottish Funding Council (SRDG HR07005) for support of this study. | en |
dc.description.abstract | This study investigated the antitumour effects of two dual mTOR/PI3K inhibitors, gedatolisib (WYE-129587/PKI-587/PF-05212384) and PF-04691502 against a panel of six human patient derived ovarian cancer xenograft models. Both dual mTOR/PI3K inhibitors demonstrated antitumour activity against all xenografts tested. The compounds produced tumour stasis during the treatment period and upon cessation of treatment, tumours re-grew. In several models, there was an initial rapid reduction of tumour volume over the first week of treatment before tumour stasis. No toxicity was observed during treatment. Biomarker studies were conducted in two xenograft models; phospho-S6 (Ser235/236) expression (as a readout of mTOR activity) was reduced over the treatment period in the responding xenograft but expression increased to control (no treatment) levels on cessation of treatment. Phospho-AKT (Ser473) expression (as a readout of PI3K) was inhibited by both drugs but less markedly so than phospho-S6 expression. Initial tumour volume reduction on treatment and regrowth rate after treatment cessation was associated with phospho-S6/total S6 expression ratio. Both drugs produced apoptosis but minimally influenced markers of proliferation (Ki67, phospho-histone H3). These results indicate that mTOR/PI3K inhibition can produce broad spectrum tumour growth stasis in ovarian cancer xenograft models during continuous chronic treatment and this is associated with apoptosis. | |
dc.format.extent | 9 | |
dc.format.extent | 1583508 | |
dc.language.iso | eng | |
dc.relation.ispartof | Scientific Reports | en |
dc.subject | RC0254 Neoplasms. Tumors. Oncology (including Cancer) | en |
dc.subject | NDAS | en |
dc.subject | SDG 3 - Good Health and Well-being | en |
dc.subject.lcc | RC0254 | en |
dc.title | Evaluation of the dual mTOR/PI3K inhibitors Gedatolisib (PF-05212384) and PF-04691502 against ovarian cancer xenograft models | en |
dc.type | Journal article | en |
dc.contributor.institution | University of St Andrews. Sir James Mackenzie Institute for Early Diagnosis | en |
dc.contributor.institution | University of St Andrews. Cellular Medicine Division | en |
dc.contributor.institution | University of St Andrews. School of Medicine | en |
dc.identifier.doi | 10.1038/s41598-019-55096-9 | |
dc.description.status | Peer reviewed | en |
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