Evidence for efficacy of new hsp90 inhibitors revealed by ex vivo culture of human prostate tumors

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, Wayne D. Tilley, Lisa M. Butler

Research output: Contribution to journalArticle

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Abstract

Purpose: 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. Experimental Design: 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. Results: 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. Conclusions: 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.

Original languageEnglish (US)
Pages (from-to)3562-3570
Number of pages9
JournalClinical Cancer Research
Volume18
Issue number13
DOIs
StatePublished - Jul 1 2012

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tanespimycin
Prostate
Prostatic Neoplasms
Neoplasms
Cell Line
Clinical Trials
Culture Techniques
Prostatectomy
Cell Death
Research Design
Therapeutics
Animal Models
Biomarkers
5-(2,4-dihydroxy-5-isopropylphenyl)-4-(4-morpholin-4-ylmethylphenyl)isoxazole-3-carboxylic acid ethylamide
2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido(4,3-d)pyrimidin-5(6H)-one
Proteins

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Centenera, M. M., Gillis, J. L., Hanson, A. R., Jindal, S., Taylor, R. A., Risbridger, G. P., ... Butler, L. M. (2012). Evidence for efficacy of new hsp90 inhibitors revealed by ex vivo culture of human prostate tumors. Clinical Cancer Research, 18(13), 3562-3570. https://doi.org/10.1158/1078-0432.CCR-12-0782

Evidence for efficacy of new hsp90 inhibitors revealed by ex vivo culture of human prostate tumors. / Centenera, Margaret M.; Gillis, Joanna L.; Hanson, Adrienne R.; Jindal, Shalini; Taylor, Renea A.; Risbridger, Gail P.; Sutherland, Peter D.; Scher, Howard I.; Raj, Ganesh V.; Knudsen, Karen E.; Yeadon, Trina; Tilley, Wayne D.; Butler, Lisa M.

In: Clinical Cancer Research, Vol. 18, No. 13, 01.07.2012, p. 3562-3570.

Research output: Contribution to journalArticle

Centenera, MM, Gillis, JL, Hanson, AR, Jindal, S, Taylor, RA, Risbridger, GP, Sutherland, PD, Scher, HI, Raj, GV, Knudsen, KE, Yeadon, T, Tilley, WD & Butler, LM 2012, 'Evidence for efficacy of new hsp90 inhibitors revealed by ex vivo culture of human prostate tumors', Clinical Cancer Research, vol. 18, no. 13, pp. 3562-3570. https://doi.org/10.1158/1078-0432.CCR-12-0782
Centenera, Margaret M. ; Gillis, Joanna L. ; Hanson, Adrienne R. ; Jindal, Shalini ; Taylor, Renea A. ; Risbridger, Gail P. ; Sutherland, Peter D. ; Scher, Howard I. ; Raj, Ganesh V. ; Knudsen, Karen E. ; Yeadon, Trina ; Tilley, Wayne D. ; Butler, Lisa M. / Evidence for efficacy of new hsp90 inhibitors revealed by ex vivo culture of human prostate tumors. In: Clinical Cancer Research. 2012 ; Vol. 18, No. 13. pp. 3562-3570.
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abstract = "Purpose: 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. Experimental Design: 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. Results: 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. Conclusions: 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.",
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AU - Taylor, Renea A.

AU - Risbridger, Gail P.

AU - Sutherland, Peter D.

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AU - Raj, Ganesh V.

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