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dc.contributor.advisorde Bono, J
dc.contributor.authorPaschalis, A
dc.date.accessioned2021-09-27T14:50:15Z
dc.date.available2021-10-30T00:00:00Z
dc.date.issued2021-04-30
dc.identifier.citation2021
dc.identifier.urihttps://repository.icr.ac.uk/handle/internal/4829
dc.description.abstractOver the past decade, androgen receptor (AR) directed therapies such as abiraterone and enzalutamide have become the standard of care for treating advanced prostate cancer, improving both progression-free and overall survival. Some patients, however, never respond to these agents, while all eventually acquire resistance, leading to invariably fatal disease progression. This resistance is in part due to the development of constitutively active alternatively spliced variants of the AR (AR-SVs) that are truncated and lack the regulatory AR ligand-binding domain; the target of current AR directed therapies. Of the many AR-SVs that have been reported, AR splice variant 7 (AR-V7) is the most prevalent and the best studied, and has been associated with resistance to AR targeting therapies and poorer overall survival. In this thesis, I describe my work focused on identifying proteins that are key to the production of AR-V7, validate my findings using clinical samples and study splicing regulatory mechanisms in in vitro models of lethal prostate cancer. Through orthogonal studies I identify the 2-oxoglutarate-dependent dioxygenase JMJD6 as a key regulator of AR-V7, as evidenced by its: 1) upregulation with in vitro androgen-deprivation-resistance; 2) downregulation alongside AR-V7 by BET inhibition; 3) being the top hit of a targeted siRNA screen of spliceosome related genes. Furthermore, I demonstrate that JMJD6 protein levels increase significantly with castration-resistance (p<0.001) and are associated with both higher levels of AR-V7 (p=0.036), and shorter median survival from castration-resistant prostate cancer (p=0.048). In vitro, I show that JMJD6 knockdown reduces prostate cancer cell growth, AR-V7 levels, and recruitment of the splicing regulatory factor U2AF65 to AR pre-mRNA. Importantly, my mutagenesis studies indicate that JMJD6 enzymatic activity is key to JMJD6-mediated AR-V7 generation, with the JMJD6 catalytic machinery residing within a druggable pocket. Taken together, I conclude that JMJD6 is a druggable target for treating advanced prostate cancer.
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.subjectProstate Cancer - Biology
dc.subjectProstate Cancer - Genetics
dc.subjectProstate Cancer - Therapy
dc.titleTargeting androgen receptor splicing in lethal prostate cancer
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.startdate2021-04-30
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 Therapeutics
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Cancer Therapeutics/Cancer Biomarkers
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Clinical Studies
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Clinical Studies/Cancer Biomarkers
pubs.organisational-group/ICR/Students
pubs.organisational-group/ICR/Students/PhD and MPhil
pubs.organisational-group/ICR/Students/PhD and MPhil/17/18 Starting Cohort
pubs.embargo.terms6 months
pubs.embargo.date2021-10-30T00:00:00Z
icr.researchteamCancer Biomarkersen_US
dc.contributor.icrauthorPaschalis, Alecen
uketdterms.institutionInstitute of Cancer Research
uketdterms.qualificationlevelDoctoral
uketdterms.qualificationnamePh.D
dc.type.qualificationlevelDoctoral
dc.type.qualificationnamePh.D


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