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dc.contributor.authorRoulstone, V
dc.date.accessioned2021-11-08T16:17:29Z
dc.date.available2022-03-30T00:00:00Z
dc.date.issued2021-09-30
dc.identifier.citation2021
dc.identifier.urihttps://repository.icr.ac.uk/handle/internal/4879
dc.description.abstractReovirus type 3 Dearing (RtD3) is an oncolytic dsRNA virus with limited single-agent activity in clinical studies but has potential for use in combination regimens. Herein, I sought to discover synergistic drug-virotherapy combinations using an unbiased screening approach that highlighted the CDK4/6 inhibitor, palbociclib, as a leading hit. Cytoplasmic nucleic acid sensors for double-standard (ds) RNA (RIG-I/MDAS) and DNA (cGAS-STING) are pattern recognition receptors (PRRs) key to intracellular anti-viral responses. Recent research has highlighted roles for PRR agonists, including oncolytic virotherapy agents, in anti-tumour immunotherapy. Combined rt3D-palbociclib treatment potently increased expression of PRRs and interferon signalling. Additionally, this combination also induced an endoplasmic reticulum (ER) stress signature. Knockdown (siRNA) studies indicated key proteins involved in the unfolded response (UPR) and the RNA sensor, RIG-I, were essential to the phenotype observed. Mechanistically independent experiments, using synthetic RNA agonists and the ER stress inducer (thapsigargin), confirmed cross-talk between RNA sensing and ER stress pathways that augment cancer cell death and interferon production. Combined Rt3D-palbociclib increased innate immune activation and effector function. These findings demonstrate that UPR signalling and innate immune RNA sensor crosstalk can be exploited to enhance anti-cancer efficacy with pro-immunogenic consequences. This has implications for future clinical development of PRR agonists and oncolytic viruses, as well as broadening the therapeutic remit of CDK4/6 inhibitors to include their role as both an ER stress and dsRNA PRR sensitiser.
dc.languageeng
dc.language.isoeng
dc.publisherInstitute of Cancer Research (University Of London)
dc.rights.urihttps://www.rioxx.net/licenses/all-rights-reserved
dc.subjectTheses, Doctoral
dc.subjectChemotherapy
dc.subjectVirotherapy
dc.subjectImmunotherapy
dc.titleBiological effects of combination therapy with oncolytic reovirus and palbociclib
dc.typeThesis or Dissertation
dcterms.accessRightsPublic
dcterms.licensehttps://www.rioxx.net/licenses/all-rights-reserved
rioxxterms.versionAO
rioxxterms.licenseref.urihttps://www.rioxx.net/licenses/all-rights-reserved
rioxxterms.licenseref.startdate2021-09-30
rioxxterms.typeThesis
pubs.notes6 months
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/Cancer Biology
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Cancer Biology/Targeted Therapy
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Radiotherapy and Imaging
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Radiotherapy and Imaging/Targeted Therapy
pubs.embargo.terms6 months
pubs.embargo.date2022-03-30T00:00:00Z
icr.researchteamTargeted Therapy
dc.contributor.icrauthorRoulstone, Victoriaen_US
uketdterms.institutionInstitute of Cancer Research
uketdterms.qualificationlevelDoctoral
uketdterms.qualificationnamePh.D
dc.type.qualificationlevelDoctoral
dc.type.qualificationnamePh.D


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