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dc.contributor.authorMaxwell, PJen_US
dc.contributor.authorMcKechnie, Men_US
dc.contributor.authorArmstrong, CWen_US
dc.contributor.authorManley, JMen_US
dc.contributor.authorOng, CWen_US
dc.contributor.authorWorthington, Jen_US
dc.contributor.authorMills, IGen_US
dc.contributor.authorLongley, DBen_US
dc.contributor.authorQuigley, JPen_US
dc.contributor.authorZoubedi, Aen_US
dc.contributor.authorde Bono, JSen_US
dc.contributor.authorDeryugina, Een_US
dc.contributor.authorLaBonte, MJen_US
dc.contributor.authorWaugh, DJJen_US
dc.date.accessioned2022-05-25T13:24:56Z
dc.date.available2022-05-25T13:24:56Z
dc.date.issued2022-03-18en_US
dc.identifier.citationMolecular cancer research : MCR, 2022, pp. molcanres.0780.2021 - ?en_US
dc.identifier.issn1541-7786en_US
dc.identifier.urihttps://repository.icr.ac.uk/handle/internal/5143
dc.identifier.eissn1557-3125en_US
dc.identifier.doi10.1158/1541-7786.mcr-21-0780en_US
dc.description.abstractInhibiting androgen-signaling using androgen signaling inhibitors (ASI) remains the primary treatment for castrate-resistant prostate cancer. Acquired resistance to androgen receptor (AR)-targeted therapy represents a major impediment to durable clinical response. Understanding resistance mechanisms, including the role of AR expressed in other cell types within the tumour microenvironment, will extend the clinical benefit of AR-targeted therapy. Here we show the ASI Enzalutamide induces vascular catastrophe and promotes hypoxia and microenvironment adaptation. We characterize treatment-induced hypoxia, and subsequent induction of angiogenesis, as novel mechanisms of relapse to Enzalutamide, highlighting the importance of two hypoxia-regulated cytokines in underpinning relapse. We confirmed AR-expression in CD34+ vascular endothelium of biopsy tissue and human vascular endothelial cells (HVEC). Enzalutamide attenuated angiogenic tubule formation and induced cytotoxicity in HVEC in vitro, and rapidly induced sustained hypoxia in LNCaP xenografts. Subsequent reoxygenation, following prolonged Enzalutamide treatment, was associated with increased tumor vessel density and accelerated tumor growth. Hypoxia increased AR expression and transcriptional activity in prostate cells in vitro. Co-inhibition of IL-8 and VEGF-A restored tumor-response in the presence of Enzalutamide, confirming the functional importance of their elevated expression in Enzalutamide-resistant (EnzR)-models. Moreover, co-inhibition of IL-8 and VEGF-A resulted in a durable, effective resolution of Enzalutamide-sensitive prostate tumors. We conclude that concurrent inhibition of two hypoxia induced factors, IL-8 and VEGF-A, prolongs tumor sensitivity to Enzalutamide in pre-clinical models and may delay the onset of Enzalutamide-resistance. Implications: Targeting hypoxia induced signaling may extend the therapeutic benefit of Enzalutamide, providing an improved treatment strategy for patients with resistant disease.en_US
dc.formatPrint-Electronicen_US
dc.format.extentmolcanres.0780.2021 - ?en_US
dc.languageengen_US
dc.language.isoengen_US
dc.titleAttenuating adaptive VEGF-A and IL-8 signaling restores durable tumor control in AR-antagonist-treated prostate cancers.en_US
dc.typeJournal Article
dcterms.dateAccepted2022-03-14en_US
rioxxterms.versionofrecord10.1158/1541-7786.mcr-21-0780en_US
rioxxterms.licenseref.startdate2022-03-18en_US
rioxxterms.typeJournal Article/Reviewen_US
dc.relation.isPartOfMolecular cancer research : MCRen_US
pubs.notesNot knownen_US
pubs.organisational-group/ICR
pubs.organisational-group/ICR/Primary Group
pubs.organisational-group/ICR/Primary Group/ICR Divisions
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Clinical Studies
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Clinical Studies/Prostate Cancer Targeted Therapy Group
pubs.publication-statusPublisheden_US
pubs.embargo.termsNot knownen_US
icr.researchteamProstate Cancer Targeted Therapy Group
dc.contributor.icrauthorDe Bono, Johannen_US


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