Abstract 2433: In vitro and in vivo antitumor activity of the next generation HSP90 inhibitor, AT13387, in both hormone-sensitive and castration-resistant prostate cancer models.

Abstract

Abstract HSP90 is a molecular chaperone involved in the conformational maturation and function of a large number of ‘client’ proteins that have been implicated in oncogenesis. The androgen receptor (AR), a key driver of prostate cancer growth and treatment resistance, is an HSP90 client and its function is dependent on HSP90 chaperone activity. The aim of this study was to evaluate the anti-tumour activity of AT13387, a novel second generation non-ansamycin HSP90 inhibitor, in prostate cancer models. AT13387 is currently being investigated in the clinic in GIST and NSCLC. It is a potent inhibitor of HSP90 (Kd 0.71 nM) and has previously been shown to inhibit proliferation and bring about the depletion of client proteins in a wide range of cell lines as well as inhibiting tumor growth in a number of xenograft models. In prostate cancer cell lines (VCaP, LNCaP, 22Rv1), AT13387 treatment depleted HSP90 clients such as AKT, HER-2 and CRAF, along with the induction of HSP72, confirming target inhibition. AT13387 treatment also resulted in depletion of mutant and wild-type AR, as well as the constitutively active truncated AR splice variant 7 (AR-V7). HSP90 inhibition disrupted AR nuclear localisation and AR transcriptional activity and resulted in down-regulation of AR-regulated genes in vitro. Inhibition of HSP90 translated into proliferative inhibition, with GI50 values in the range of 15-70 nM, and induction of apoptosis. AT13387 showed substantially greater potency than the first generation, natural product-based HSP90 inhibitor 17-AAG in modulating HSP90 client proteins, inhibiting cell growth and inducing cell death. The anti-tumor activity of AT13387 was demonstrated in vivo in a human xenograft model of castration-resistant prostate cancer. Our data suggest that HSP90 inhibition, through the use of more potent and better tolerated HSP90 inhibitors, will be active in multi drug resistant prostate cancer. These led to the design of a Phase I/II clinical trial of AT13387 with and without abiraterone acetate in castration-resistant prostate cancer no longer responding to abiraterone that is now accruing patients (NCT01685268). Citation Format: Roberta Ferraldeschi, Somaieh Hedayat, Tomoko Smyth, Nicola Wallis, John Lyons, Ruth Riisnaes, Mateus Crespo, Daniel Nava Rodrigues, Susana Miranda, Swee Sharp, Gerhardt Attard, Suzanne Eccles, Paul Workman, Johann de Bono. In vitro and in vivo antitumor activity of the next generation HSP90 inhibitor, AT13387, in both hormone-sensitive and castration-resistant prostate cancer models. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2433. doi:10.1158/1538-7445.AM2013-2433