dc.contributor.author | Neeb, A | |
dc.contributor.author | Figueiredo, I | |
dc.contributor.author | Bogdan, D | |
dc.contributor.author | Cato, L | |
dc.contributor.author | Stober, J | |
dc.contributor.author | Jiménez-Vacas, JM | |
dc.contributor.author | Gourain, V | |
dc.contributor.author | Lee, II | |
dc.contributor.author | Seeger, R | |
dc.contributor.author | Muhle-Goll, C | |
dc.contributor.author | Gurel, B | |
dc.contributor.author | Welti, J | |
dc.contributor.author | Nava Rodrigues, D | |
dc.contributor.author | Rekowski, J | |
dc.contributor.author | Qiu, X | |
dc.contributor.author | Jiang, Y | |
dc.contributor.author | Di Micco, P | |
dc.contributor.author | Mateos, B | |
dc.contributor.author | Bielskutė, S | |
dc.contributor.author | Riisnaes, R | |
dc.contributor.author | Ferreira, A | |
dc.contributor.author | Miranda, S | |
dc.contributor.author | Crespo, M | |
dc.contributor.author | Buroni, L | |
dc.contributor.author | Ning, J | |
dc.contributor.author | Carreira, S | |
dc.contributor.author | Bräse, S | |
dc.contributor.author | Jung, N | |
dc.contributor.author | Gräßle, S | |
dc.contributor.author | Swain, A | |
dc.contributor.author | Salvatella, X | |
dc.contributor.author | Plymate, SR | |
dc.contributor.author | Al-Lazikani, B | |
dc.contributor.author | Long, HW | |
dc.contributor.author | Yuan, W | |
dc.contributor.author | Brown, M | |
dc.contributor.author | Cato, ACB | |
dc.contributor.author | de Bono, JS | |
dc.contributor.author | Sharp, A | |
dc.coverage.spatial | United States | |
dc.date.accessioned | 2024-07-03T14:27:57Z | |
dc.date.available | 2024-07-03T14:27:57Z | |
dc.date.issued | 2024-06-04 | |
dc.identifier | 734951 | |
dc.identifier.citation | Molecular Cancer Therapeutics, 2024, 23 (6), pp. 791 - 808 | en_US |
dc.identifier.issn | 1535-7163 | |
dc.identifier.uri | https://repository.icr.ac.uk/handle/internal/6296 | |
dc.identifier.eissn | 1538-8514 | |
dc.identifier.eissn | 1538-8514 | |
dc.identifier.doi | 10.1158/1535-7163.MCT-23-0354 | |
dc.identifier.doi | 10.1158/1535-7163.MCT-23-0354 | |
dc.description.abstract | Therapies that abrogate persistent androgen receptor (AR) signaling in castration-resistant prostate cancer (CRPC) remain an unmet clinical need. The N-terminal domain of the AR that drives transcriptional activity in CRPC remains a challenging therapeutic target. Herein we demonstrate that BCL-2-associated athanogene-1 (BAG-1) mRNA is highly expressed and associates with signaling pathways, including AR signaling, that are implicated in the development and progression of CRPC. In addition, interrogation of geometric and physiochemical properties of the BAG domain of BAG-1 isoforms identifies it to be a tractable but challenging drug target. Furthermore, through BAG-1 isoform mouse knockout studies, we confirm that BAG-1 isoforms regulate hormone physiology and that therapies targeting the BAG domain will be associated with limited "on-target" toxicity. Importantly, the postulated inhibitor of BAG-1 isoforms, Thio-2, suppressed AR signaling and other important pathways implicated in the development and progression of CRPC to reduce the growth of treatment-resistant prostate cancer cell lines and patient-derived models. However, the mechanism by which Thio-2 elicits the observed phenotype needs further elucidation as the genomic abrogation of BAG-1 isoforms was unable to recapitulate the Thio-2-mediated phenotype. Overall, these data support the interrogation of related compounds with improved drug-like properties as a novel therapeutic approach in CRPC, and further highlight the clinical potential of treatments that block persistent AR signaling which are currently undergoing clinical evaluation in CRPC. | |
dc.format | Print | |
dc.format.extent | 791 - 808 | |
dc.language | eng | |
dc.language.iso | eng | en_US |
dc.publisher | AMER ASSOC CANCER RESEARCH | en_US |
dc.relation.ispartof | Molecular Cancer Therapeutics | |
dc.rights.uri | http://creativecommons.org/licenses/by/4.0/ | en_US |
dc.subject | Male | |
dc.subject | Prostatic Neoplasms, Castration-Resistant | |
dc.subject | Humans | |
dc.subject | Animals | |
dc.subject | Mice | |
dc.subject | Signal Transduction | |
dc.subject | Disease Progression | |
dc.subject | Receptors, Androgen | |
dc.subject | Cell Line, Tumor | |
dc.subject | DNA-Binding Proteins | |
dc.subject | Transcription Factors | |
dc.subject | Cell Proliferation | |
dc.subject | Xenograft Model Antitumor Assays | |
dc.subject | Gene Expression Regulation, Neoplastic | |
dc.title | Thio-2 Inhibits Key Signaling Pathways Required for the Development and Progression of Castration-resistant Prostate Cancer. | en_US |
dc.type | Journal Article | |
dcterms.dateAccepted | 2024-02-22 | |
dc.date.updated | 2024-07-03T14:27:22Z | |
rioxxterms.version | VoR | en_US |
rioxxterms.versionofrecord | 10.1158/1535-7163.MCT-23-0354 | en_US |
rioxxterms.licenseref.startdate | 2024-06-04 | |
rioxxterms.type | Journal Article/Review | en_US |
pubs.author-url | https://www.ncbi.nlm.nih.gov/pubmed/38412481 | |
pubs.issue | 6 | |
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/Development & Cancer | |
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/Cancer Therapeutics/Computational Biology and Chemogenomics | |
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/Molecular Pathology | |
pubs.organisational-group | ICR/Primary Group/ICR Divisions/Molecular Pathology/Development & Cancer | |
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.organisational-group | ICR/ImmNet | |
pubs.organisational-group | ICR/Students/PhD and MPhil/22/23 Starting Cohort | |
pubs.publication-status | Published | |
pubs.publisher-url | http://dx.doi.org/10.1158/1535-7163.mct-23-0354 | |
pubs.volume | 23 | |
icr.researchteam | Cancer Biomarkers | en_US |
icr.researchteam | Development & Cancer | en_US |
icr.researchteam | Computational Biology | en_US |
icr.researchteam | PrCa Targeted Therapy | en_US |
icr.researchteam | Translational Therapeutic | en_US |
dc.contributor.icrauthor | Bogdan, Denisa Ioana | |
dc.contributor.icrauthor | Gurel, Bora | |
dc.contributor.icrauthor | Miranda, Susana | |
dc.contributor.icrauthor | Carreira, Suzanne | |
dc.contributor.icrauthor | Swain, Amanda | |
dc.contributor.icrauthor | Al-Lazikani, Bissan | |
dc.contributor.icrauthor | De Bono, Johann | |
dc.contributor.icrauthor | Sharp, Adam | |
icr.provenance | Deposited by Mr Arek Surman on 2024-07-03. Deposit type is initial. No. of files: 1. Files: Thio-2 Inhibits Key Signaling Pathways Required for the Development and Progression of Castration-resistant Prostate Cancer.pdf | |