Evidence for efficacy of new Hsp90 inhibitors revealed by ex vivo culture of human prostate tumors.

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.

• Authors: 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, Australian Prostate Cancer BioResource, Wayne D Tilley, Lisa M Butler
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 18 Issue 13 Pg. 3562-70 (Jul 01 2012) ISSN: 1557-3265 [Electronic] United States
• PMID: 22573351 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: ©2012 AACR.

Chemical References

• 2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido(4,3-d)pyrimidin-5(6H)-one
• 5-(2,4-dihydroxy-5-isopropylphenyl)-4-(4-morpholin-4-ylmethylphenyl)isoxazole-3-carboxylic acid ethylamide
• Antineoplastic Agents
• Benzoquinones
• HSP70 Heat-Shock Proteins
• HSP90 Heat-Shock Proteins
• Isoxazoles
• Lactams, Macrocyclic
• Pyridones
• Pyrimidines
• Resorcinols
• tanespimycin

Topics

• Aged
• Antineoplastic Agents (pharmacology)
• Apoptosis (drug effects)
• Benzoquinones (pharmacology)
• Cell Proliferation (drug effects)
• Cell Survival (drug effects)
• Drug Evaluation, Preclinical
• G2 Phase Cell Cycle Checkpoints (drug effects)
• Gene Expression (drug effects)
• HSP70 Heat-Shock Proteins (genetics, metabolism)
• HSP90 Heat-Shock Proteins (antagonists & inhibitors)
• Humans
• Isoxazoles (pharmacology)
• Lactams, Macrocyclic (pharmacology)
• Male
• Middle Aged
• Molecular Targeted Therapy
• Prostatic Neoplasms (drug therapy, metabolism)
• Pyridones (pharmacology)
• Pyrimidines (pharmacology)
• Resorcinols (pharmacology)
• Tissue Culture Techniques
• Tumor Cells, Cultured (drug effects)