Please use this identifier to cite or link to this item: http://hdl.handle.net/2440/73280
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dc.contributor.authorCentenera, M.en
dc.contributor.authorGillis, J.en
dc.contributor.authorHanson, A.en
dc.contributor.authorJindal, S.en
dc.contributor.authorTaylor, R.en
dc.contributor.authorRisbridger, G.en
dc.contributor.authorSutherland, P.en
dc.contributor.authorScher, H.en
dc.contributor.authorRaj, G.en
dc.contributor.authorKnudsen, K.en
dc.contributor.authorYeadon, T.en
dc.contributor.authorTilley, W.en
dc.contributor.authorButler, L.en
dc.date.issued2012en
dc.identifier.citationClinical Cancer Research, 2012; 18(13):3562-3570en
dc.identifier.issn1078-0432en
dc.identifier.issn1557-3265en
dc.identifier.urihttp://hdl.handle.net/2440/73280-
dc.description.abstract<h4>Purpose</h4>Targeting Hsp90 has significant potential as a treatment for prostate cancer, but prototypical agents such as 17-allylamino-17 demethoxygeldanamycin (17-AAG) have been ineffective in clinical trials. Recently, a phase I study aimed at defining a biologically active dose reported the first response to an Hsp90 inhibitor in a patient with prostate cancer, which supports the development of new generation compounds for this disease.<h4>Experimental design</h4>The biological actions of two new synthetic Hsp90 inhibitors, NVP-AUY922 and NVP-HSP990, were evaluated in the prostate cancer cell lines PC-3, LNCaP, and VCaP and in an ex vivo culture model of human prostate cancer.<h4>Results</h4>In cell lines, both NVP-AUY922 and NVP-HSP990 showed greater potency than 17-AAG with regard to modulation of Hsp90 client proteins, inhibition of proliferation, and induction of apoptotic cell death. In prostate tumors obtained from radical prostatectomy that were cultured ex vivo, treatment with 500 nmol/L of NVP-AUY922, NVP-HSP990, or 17-AAG caused equivalent target modulation, determined by the pharmacodynamic marker Hsp70, but only NVP-AUY922 and NVP-HSP990 showed antiproliferative and proapoptotic activity.<h4>Conclusions</h4>This study provides some of the first evidence that new generation Hsp90 inhibitors are capable of achieving biologic responses in human prostate tumors, with both NVP-AUY922 and NVP-HSP990 showing potent on-target efficacy. Importantly, the ex vivo culture technique has provided information on Hsp90 inhibitor action not previously observed in cell lines or animal models. This approach, therefore, has the potential to enable more rational selection of therapeutic agents and biomarkers of response for clinical trials.en
dc.description.statementofresponsibilityMargaret M. Centenera, Joanna L. Gillis, Adrienne R. Hanson, Shalini Jindal, Renea A. Taylor, Gail P. Risbridger, Peter D. Sutherland, Howard I. Scher, Ganesh V. Raj, Karen E. Knudsen, Trina Yeadon for the Australian Prostate Cancer BioResource, Wayne D. Tilley, and Lisa M. Butleren
dc.language.isoenen
dc.publisherAmer Assoc Cancer Researchen
dc.rights© 2012 American Association for Cancer Research.en
dc.subjectAustralian Prostate Cancer BioResource; Tumor Cells, Cultured; Humans; Prostatic Neoplasms; Lactams, Macrocyclic; Resorcinols; Benzoquinones; Isoxazoles; Pyridones; Pyrimidines; Antineoplastic Agents; Tissue Culture Techniques; Drug Evaluation, Preclinical; Apoptosis; Cell Proliferation; Cell Survival; Gene Expression; Aged; Middle Aged; Male; HSP70 Heat-Shock Proteins; HSP90 Heat-Shock Proteins; Molecular Targeted Therapy; G2 Phase Cell Cycle Checkpointsen
dc.titleEvidence for efficacy of new Hsp90 inhibitors revealed by ex vivo culture of human prostate tumorsen
dc.typeJournal articleen
dc.identifier.rmid0020120716en
dc.identifier.doi10.1158/1078-0432.CCR-12-0782en
dc.identifier.pubid23845-
pubs.library.collectionMedicine publicationsen
pubs.verification-statusVerifieden
pubs.publication-statusPublisheden
dc.identifier.orcidCentenera, M. [0000-0002-2206-0632]en
dc.identifier.orcidTilley, W. [0000-0003-1893-2626]en
dc.identifier.orcidButler, L. [0000-0003-2698-3220]en
Appears in Collections:Medicine publications

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