Abstract
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. 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. 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. 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.
Highlights
The molecular chaperone Hsp90 is responsible for folding and stabilizing client proteins into their active conformation
The objective of this study was to compare the potential of AUY922 and HSP990 with 17-AAG to modulate Hsp90 client proteins and influence proliferation and death of prostate cancer cells, in vitro, and in ex vivo cultures of human primary tumors
AUY922 and HSP990 were obtained from Novartis and dissolved in dimethyl sulfoxide (DMSO). 17-AAG was obtained from the National Cancer Institute and dissolved in DMSO
Summary
The molecular chaperone Hsp is responsible for folding and stabilizing client proteins into their active conformation. The androgen receptor, the key driver of prostate cancer progression [3], is an Hsp client protein. The ansamycin derivatives 17-allylamino-17 demethoxygeldanamycin (17-AAG) and 17 - (dimethylaminotheyl -amino) -17 - demethoxygeldanamycin (17-DMAG) are the most extensively characterized Hsp inhibitors. Their clinical failure has been attributed to poor solubility and pharmacokinetics, hepatotoxicity and susceptibility to MDR [10]. The first response to an Hsp inhibitor in a patient with castration-resistant prostate cancer (CRPC) was recently reported in a phase I trial of 17-DMAG that aimed to define a biologically effective dose rather than maximum tolerated dose
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