Please use this identifier to cite or link to this item: https://hdl.handle.net/2440/73280
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Type: Journal article
Title: Evidence for efficacy of new Hsp90 inhibitors revealed by ex vivo culture of human prostate tumors
Author: Centenera, M.
Gillis, J.
Hanson, A.
Jindal, S.
Taylor, R.
Risbridger, G.
Sutherland, P.
Scher, H.
Raj, G.
Knudsen, K.
Yeadon, T.
Tilley, W.
Butler, L.
Citation: Clinical Cancer Research, 2012; 18(13):3562-3570
Publisher: Amer Assoc Cancer Research
Issue Date: 2012
ISSN: 1078-0432
1557-3265
Statement of
Responsibility: 
Margaret 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. Butler
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.
Keywords: Australian 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 Checkpoints
Rights: © 2012 American Association for Cancer Research.
DOI: 10.1158/1078-0432.CCR-12-0782
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