Abstract 4512: The novel HSP90 inhibitor, PF-04929113, inhibits AR activity and osteoclastogenesis and delays castrate-resistant LNCaP prostate cancer tumor growth

Abstract

Abstract Introduction and Objective: Prostate cancer responds initially to anti-androgen therapies, however, progression to castration resistant disease frequently occurs. Consequently there is an urgent need for novel therapeutic agents that can prevent the emergence of the castration resistant form of disease. Heat shock protein (HSP) 90 is a molecular chaperone involved in the maturation and stability of the Androgen Receptor (AR). In this study, we assessed the in vitro and in vivo antitumor properties of a novel synthetic HSP90 inhibitor, PF-04928473 in vitro and PF-04929113 in vivo, in prostate cancer and bone metastasis development. Methods: The effects of the HSP90 inhibitor were evaluated in vitro on LNCaP, C4-2, PC3 and DU145 cell growth and apoptosis. AR transactivation and other biochemical assays studied AR/HSP90 interaction. The consequence of HSP90 therapy in vivo was evaluated in athymic mice bearing castration resistant LNCaP xenografts. The consequence of PF-04928473 therapy on bone metastasis was studied using a osteoclastogenesis in vitro assay. Results: In our panel of prostate tumor cell lines, PF-04928473 inhibited cell growth in a dose-dependent manner (IC50 ± 30nM) and induced apoptosis with an increase of sub-G1 fraction and PARP cleavage. These biologic events were accompanied by decreased expression of AR and PSA, AR transactivation, inhibition of Akt and Erk activation, and modulation of HSP expression. When administered orally 3 times/week (50mg/kg) to mice bearing castration resistant LNCaP tumors, PF-04929113 significantly inhibited tumor growth by 160% and prolonged survival compared to controls, but a small reduction in total bodyweight was observed. In contrast to 17-AAG, the novel PF-04928473 compound was not observed to activate src but did block osteoclast differentiation in vitro. Conclusions: Targeting HSP90 using PF-04928473 and PF-04929113 inhibited castration resistant LNCaP tumor growth in vitro and in vivo in part through a mechanism involving disruption of the AR signaling axis and appears to inhibit bone metastasis by blocking osteoclastogenesis. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4512.