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dc.contributor.authorRodrigues, DN
dc.contributor.authorBoysen, G
dc.contributor.authorSumanasuriya, S
dc.contributor.authorSeed, G
dc.contributor.authorMarzo, AMD
dc.contributor.authorde Bono, J
dc.date.accessioned2018-02-14T15:10:17Z
dc.date.issued2017-01
dc.identifier.citationThe Journal of pathology, 2017, 241 (2), pp. 173 - 182
dc.identifier.issn0022-3417
dc.identifier.urihttps://repository.icr.ac.uk/handle/internal/1083
dc.identifier.eissn1096-9896
dc.identifier.doi10.1002/path.4826
dc.description.abstractProstate cancer (PCa) is a clinically heterogeneous disease and current treatment strategies are based largely on anatomical and pathological parameters. In the recent past, several DNA sequencing studies of primary and advanced PCa have revealed recurrent patterns of genomic aberrations that expose mechanisms of resistance to available therapies and potential new drug targets. Suppression of androgen receptor (AR) signalling is the cornerstone of advanced prostate cancer treatment. Genomic aberrations of the androgen receptor or alternative splicing of its mRNA are increasingly recognised as biomarkers of resistance to AR-targeted therapies such as abiraterone or enzalutamide. Genomic aberrations of the PI3K-AKT axis, in particular affecting PTEN, are common in PCa, and compounds targeting different kinases in this pathway are showing promise in clinical trials. Both germline and somatic defects in DNA repair genes have been shown to sensitise some patients to therapy with PARP inhibition. In addition, abnormalities in mismatch-repair genes are associated with response to immune checkpoint inhibition in other solid tumours and present a tantalising therapeutic avenue to be pursued. Aberrations in CDK4/6-RB1 pathway genes occur in a subset of PCas, may associate with differential sensitivity to treatment, and are likely to have clinical implications beyond prognostication. Inhibitors of CDK4/6 are already being tested in prostate cancer clinical trials. Furthermore, deletions of RB1 are strongly associated with a neuroendocrine phenotype, a rare condition characterized by a non-AR-driven transcriptomic profile. Finally, aberrations in genes involved in regulating the chromatin structure are an emerging area of interest. Deletions of CHD1 are not infrequent in PCa and may associate with increased AR activity and genomic instability, and these tumours could benefit from DNA-damaging therapies. This review summarises how genomic discoveries in PCa are changing the treatment landscape of advanced CRPC, both by identifying biomarkers of resistance and by identifying vulnerabilities to be targeted. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
dc.formatPrint-Electronic
dc.format.extent173 - 182
dc.languageeng
dc.language.isoeng
dc.subjectAnimals
dc.subjectHumans
dc.subjectProstatic Neoplasms
dc.subjectAndrostenes
dc.subjectReceptors, Androgen
dc.subjectSignal Transduction
dc.subjectMale
dc.subjectPhosphatidylinositol 3-Kinases
dc.subjectBiomarkers
dc.titleThe molecular underpinnings of prostate cancer: impacts on management and pathology practice.
dc.typeJournal Article
dcterms.dateAccepted2016-10-01
rioxxterms.versionofrecord10.1002/path.4826
rioxxterms.licenseref.startdate2017-01
rioxxterms.typeJournal Article/Review
dc.relation.isPartOfThe Journal of pathology
pubs.issue2
pubs.notesNot known
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/Primary Group/ICR Divisions/Clinical Studies/Prostate Cancer Targeted Therapy Group
pubs.organisational-group/ICR/Primary Group/Royal Marsden Clinical Units
pubs.organisational-group/ICR/Students
pubs.organisational-group/ICR/Students/PhD and MPhil
pubs.organisational-group/ICR/Students/PhD and MPhil/16/17 Starting Cohort
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/Primary Group/ICR Divisions/Clinical Studies/Prostate Cancer Targeted Therapy Group
pubs.organisational-group/ICR/Primary Group/Royal Marsden Clinical Units
pubs.organisational-group/ICR/Students
pubs.organisational-group/ICR/Students/PhD and MPhil
pubs.organisational-group/ICR/Students/PhD and MPhil/16/17 Starting Cohort
pubs.publication-statusPublished
pubs.volume241
pubs.embargo.termsNot known
icr.researchteamCancer Biomarkersen_US
icr.researchteamProstate Cancer Targeted Therapy Groupen_US
dc.contributor.icrauthorSumanasuriya, Seminien
dc.contributor.icrauthorSeed, Georgeen
dc.contributor.icrauthorDe Bono, Johannen
dc.contributor.icrauthorMarsden,en
dc.contributor.icrauthorNava Rodrigues, Danielen


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