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dc.contributor.authorSheehan, B
dc.contributor.authorNeeb, A
dc.contributor.authorBuroni, L
dc.contributor.authorPaschalis, A
dc.contributor.authorRiisnaes, R
dc.contributor.authorGurel, B
dc.contributor.authorGil, V
dc.contributor.authorMiranda, S
dc.contributor.authorCrespo, M
dc.contributor.authorGuo, C
dc.contributor.authorJiménez Vacas, J
dc.contributor.authorFigueiredo, I
dc.contributor.authorFerreira, A
dc.contributor.authorWelti, J
dc.contributor.authorYuan, W
dc.contributor.authorCarreira, S
dc.contributor.authorSharp, A
dc.contributor.authorde Bono, J
dc.coverage.spatialUnited States
dc.date.accessioned2022-07-19T10:20:39Z
dc.date.available2022-07-19T10:20:39Z
dc.date.issued2022-07-15
dc.identifier698876
dc.identifier.citationClinical Cancer Research, 2022, 28 (14), pp. 3104 - 3115
dc.identifier.issn1078-0432
dc.identifier.urihttps://repository.icr.ac.uk/handle/internal/5242
dc.identifier.eissn1557-3265
dc.identifier.eissn1557-3265
dc.identifier.doi10.1158/1078-0432.CCR-21-4531
dc.description.abstractPURPOSE: Prostate-specific membrane antigen (PSMA) targeting therapies such as Lutetium-177 (177Lu)-PSMA-617 are affecting outcomes from metastatic castration-resistant prostate cancer (mCRPC). However, a significant subset of patients have prostate cancer cells lacking PSMA expression, raising concerns about treatment resistance attributable at least in part to heterogeneous PSMA expression. We have previously demonstrated an association between high PSMA expression and DNA damage repair defects in mCRPC biopsies and therefore hypothesized that DNA damage upregulates PSMA expression. EXPERIMENTAL DESIGN: To test this relationship between PSMA and DNA damage we conducted a screen of 147 anticancer agents (NCI/NIH FDA-approved anticancer "Oncology Set") and treated tumor cells with repeated ionizing irradiation. RESULTS: The topoisomerase-2 inhibitors, daunorubicin and mitoxantrone, were identified from the screen to upregulate PSMA protein expression in castration-resistant LNCaP95 cells; this result was validated in vitro in LNCaP, LNCaP95, and 22Rv1 cell lines and in vivo using an mCRPC patient-derived xenograft model CP286 identified to have heterogeneous PSMA expression. As double-strand DNA break induction by topoisomerase-2 inhibitors upregulated PSMA, we next studied the impact of ionizing radiation on PSMA expression; this also upregulated PSMA protein expression in a dose-dependent fashion. CONCLUSIONS: The results presented herein are the first, to our knowledge, to demonstrate that PSMA is upregulated in response to double-strand DNA damage by anticancer treatment. These data support the study of rational combinations that maximize the antitumor activity of PSMA-targeted therapeutic strategies by upregulating PSMA.
dc.formatPrint
dc.format.extent3104 - 3115
dc.languageeng
dc.language.isoeng
dc.publisherAMER ASSOC CANCER RESEARCH
dc.relation.ispartofClinical Cancer Research
dc.rights.urihttps://creativecommons.org/licenses/by-nc-nd/4.0/
dc.titleProstate-Specific Membrane Antigen Expression and Response to DNA Damaging Agents in Prostate Cancer.
dc.typeJournal Article
dcterms.dateAccepted2022-05-09
dc.date.updated2022-07-19T10:20:00Z
rioxxterms.versionVoR
rioxxterms.versionofrecord10.1158/1078-0432.CCR-21-4531
rioxxterms.licenseref.startdate2022-05-12
rioxxterms.typeJournal Article/Review
pubs.author-urlhttps://www.ncbi.nlm.nih.gov/pubmed/35552383
pubs.issue14
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/ICR Divisions/Clinical Studies/Translational Therapeutics
pubs.organisational-group/ICR/Students
pubs.organisational-group/ICR/Students/PhD and MPhil
pubs.organisational-group/ICR/Students/PhD and MPhil/18/19 Starting Cohort
pubs.organisational-group/ICR/Students/PhD and MPhil/20/21 Starting Cohort
pubs.publication-statusPublished online
pubs.volume28
icr.researchteamCancer Biomarkers
icr.researchteamPrCa Targeted Therapy
icr.researchteamTranslational Therapeutic
dc.contributor.icrauthorGurel, Bora
dc.contributor.icrauthorMiranda, Susana
dc.contributor.icrauthorGuo, Wei Yu
dc.contributor.icrauthorCarreira, Suzanne
dc.contributor.icrauthorSharp, Adam
dc.contributor.icrauthorDe Bono, Johann
icr.provenanceDeposited by Mr Arek Surman on 2022-07-19. Deposit type is initial. No. of files: 1. Files: 3104.pdf


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Except where otherwise noted, this item's license is described as https://creativecommons.org/licenses/by-nc-nd/4.0/