FRINK Linked Data Fragments server

Matches in SemOpenAlex for { <https://semopenalex.org/work/W2891762892> ?p ?o ?g. }

• W2891762892 abstract "Background/Introduction: Androgen receptor (AR) signaling is a distinctive feature of prostate cancer (PC) and represents the major therapeutic target for treating metastatic prostate cancer (mPC). Though highly effective, AR antagonism can produce tumors that bypass a functional requirement for AR, often through neuroendocrine (NE) transdifferentiation. Through the molecular assessment of mPCs over two decades, we find that a phenotypic shift has occurred in mPC with the emergence of an AR-null NE-null phenotype. We sought to identify drivers of these “double-negative” PCs (DNPC), with the ultimate objective of developing therapeutic strategies. Methods: We used genome-wide profiling of copy number (array CGH), mutations (whole-exome sequencing-WES), and gene expression (RNA-seq) to compare the molecular landscapes of AR-active PC (ARPC), NEPC, and DNPC in tumors obtained from 84 consecutive men with mPC undergoing a rapid autopsy. We developed model systems including DNPC patient-derived xenografts (PDX) and cell lines that are devoid of AR activity and lack NE features. Using these models, we tested therapeutics hypothesized to inhibit the activity of pathways preferentially active in DNPC. Results: In the era prior to the approval of the AR pathway antagonists enzalutamide and abiraterone, most CRPCs were ARPCs (85%) with rare NEPCs (10%) and rarer DNPCs (5%). In the contemporary era (2012-2016), we observed a shift in tumor phenotypes with a higher representation of DNPCs. Gene expression programs of the tumors classified by IHC supported these distinct subtypes. DNPCs did not exhibit GR activity or PI3K/AKT activation but were notable for high MAPK and FGF pathway activity. Models systems recapitulated these findings. FGFR antagonists differentially repressed the growth of DNPC tumors in vitro and in vivo. Conclusions: Though the majority of mPCs that resist AR targeting retain AR signaling, an increasingly common subtype of mPC exhibits a DNPC phenotype. Our results indicate that at least a subset of these DNPCs are driven by FGF signaling and MAPK activation. Targeting the FGF axis may represent a therapeutic approach for those cancers resistant to AR-directed therapies and may circumvent treatment resistance if combined with initial AR pathway blockade. Citation Format: Colm Morrissey, Eric G. Bluemn, Ilsa M. Coleman, Jared M. Lucas, Roger T. Coleman, Robin Tharakan, Daniella Bianchi-Frias, Ruth F. Dumpit, Arja Kaipainen, Alexandra N. Corella, Yu Chi Yang, Michael D. Nyquist, Elahe Mostaghel, Xiaotun Zhang, Eva Corey, Lisha G. Brown, Holly M. Nguyen, Michael Schweizer, Lawrence D. True, Paul S. Rennie, Robert L. Vessella, Peter S. Nelson. AR is ablated: Now what? Targeting the double-negative phenotype [abstract]. In: Proceedings of the AACR Special Conference: Prostate Cancer: Advances in Basic, Translational, and Clinical Research; 2017 Dec 2-5; Orlando, Florida. Philadelphia (PA): AACR; Cancer Res 2018;78(16 Suppl):Abstract nr IA21." @default.
• W2891762892 created "2018-09-27" @default.
• W2891762892 creator A5002466627 @default.
• W2891762892 creator A5008699306 @default.
• W2891762892 creator A5014047283 @default.
• W2891762892 creator A5014339741 @default.
• W2891762892 creator A5014909897 @default.
• W2891762892 creator A5018745405 @default.
• W2891762892 creator A5020727899 @default.
• W2891762892 creator A5022292569 @default.
• W2891762892 creator A5034997866 @default.
• W2891762892 creator A5035481357 @default.
• W2891762892 creator A5043364780 @default.
• W2891762892 creator A5046195526 @default.
• W2891762892 creator A5046481049 @default.
• W2891762892 creator A5051632643 @default.
• W2891762892 creator A5057037633 @default.
• W2891762892 creator A5067800417 @default.
• W2891762892 creator A5071509387 @default.
• W2891762892 creator A5076980825 @default.
• W2891762892 creator A5076988055 @default.
• W2891762892 creator A5077753752 @default.
• W2891762892 creator A5079338108 @default.
• W2891762892 creator A5088583553 @default.
• W2891762892 date "2018-08-14" @default.
• W2891762892 modified "2023-10-13" @default.
• W2891762892 title "Abstract IA21: AR is ablated: Now what? Targeting the double-negative phenotype" @default.
• W2891762892 doi "https://doi.org/10.1158/1538-7445.prca2017-ia21" @default.
• W2891762892 hasPublicationYear "2018" @default.
• W2891762892 type Work @default.
• W2891762892 sameAs 2891762892 @default.
• W2891762892 citedByCount "0" @default.
• W2891762892 crossrefType "proceedings-article" @default.
• W2891762892 hasAuthorship W2891762892A5002466627 @default.
• W2891762892 hasAuthorship W2891762892A5008699306 @default.
• W2891762892 hasAuthorship W2891762892A5014047283 @default.
• W2891762892 hasAuthorship W2891762892A5014339741 @default.
• W2891762892 hasAuthorship W2891762892A5014909897 @default.
• W2891762892 hasAuthorship W2891762892A5018745405 @default.
• W2891762892 hasAuthorship W2891762892A5020727899 @default.
• W2891762892 hasAuthorship W2891762892A5022292569 @default.
• W2891762892 hasAuthorship W2891762892A5034997866 @default.
• W2891762892 hasAuthorship W2891762892A5035481357 @default.
• W2891762892 hasAuthorship W2891762892A5043364780 @default.
• W2891762892 hasAuthorship W2891762892A5046195526 @default.
• W2891762892 hasAuthorship W2891762892A5046481049 @default.
• W2891762892 hasAuthorship W2891762892A5051632643 @default.
• W2891762892 hasAuthorship W2891762892A5057037633 @default.
• W2891762892 hasAuthorship W2891762892A5067800417 @default.
• W2891762892 hasAuthorship W2891762892A5071509387 @default.
• W2891762892 hasAuthorship W2891762892A5076980825 @default.
• W2891762892 hasAuthorship W2891762892A5076988055 @default.
• W2891762892 hasAuthorship W2891762892A5077753752 @default.
• W2891762892 hasAuthorship W2891762892A5079338108 @default.
• W2891762892 hasAuthorship W2891762892A5088583553 @default.
• W2891762892 hasConcept C104317684 @default.
• W2891762892 hasConcept C121608353 @default.
• W2891762892 hasConcept C127716648 @default.
• W2891762892 hasConcept C16671776 @default.
• W2891762892 hasConcept C2776551883 @default.
• W2891762892 hasConcept C2777609662 @default.
• W2891762892 hasConcept C2780192828 @default.
• W2891762892 hasConcept C502942594 @default.
• W2891762892 hasConcept C54355233 @default.
• W2891762892 hasConcept C61367390 @default.
• W2891762892 hasConcept C62478195 @default.
• W2891762892 hasConcept C71924100 @default.
• W2891762892 hasConcept C86554907 @default.
• W2891762892 hasConcept C86803240 @default.
• W2891762892 hasConceptScore W2891762892C104317684 @default.
• W2891762892 hasConceptScore W2891762892C121608353 @default.
• W2891762892 hasConceptScore W2891762892C127716648 @default.
• W2891762892 hasConceptScore W2891762892C16671776 @default.
• W2891762892 hasConceptScore W2891762892C2776551883 @default.
• W2891762892 hasConceptScore W2891762892C2777609662 @default.
• W2891762892 hasConceptScore W2891762892C2780192828 @default.
• W2891762892 hasConceptScore W2891762892C502942594 @default.
• W2891762892 hasConceptScore W2891762892C54355233 @default.
• W2891762892 hasConceptScore W2891762892C61367390 @default.
• W2891762892 hasConceptScore W2891762892C62478195 @default.
• W2891762892 hasConceptScore W2891762892C71924100 @default.
• W2891762892 hasConceptScore W2891762892C86554907 @default.
• W2891762892 hasConceptScore W2891762892C86803240 @default.
• W2891762892 hasLocation W28917628921 @default.
• W2891762892 hasOpenAccess W2891762892 @default.
• W2891762892 hasPrimaryLocation W28917628921 @default.
• W2891762892 hasRelatedWork W1005262890 @default.
• W2891762892 hasRelatedWork W2080126527 @default.
• W2891762892 hasRelatedWork W2165300664 @default.
• W2891762892 hasRelatedWork W2335544039 @default.
• W2891762892 hasRelatedWork W2886843176 @default.
• W2891762892 hasRelatedWork W2891762892 @default.
• W2891762892 hasRelatedWork W2891899887 @default.
• W2891762892 hasRelatedWork W2964966565 @default.
• W2891762892 hasRelatedWork W3138616138 @default.
• W2891762892 hasRelatedWork W4282962473 @default.
• W2891762892 isParatext "false" @default.
• W2891762892 isRetracted "false" @default.
• W2891762892 magId "2891762892" @default.
• W2891762892 workType "article" @default.