Abstract 1595: Use of MDV3100 to establish androgen-receptor antagonist resistant LNCaP cells for modelling castrate-resistant progression

Abstract

Abstract Background. The androgen receptor (AR) plays a critical role in the development and progression of prostate cancer. Even in castrate resistant prostate cancer (CRPC), the AR is active and drives progression. MDV3100 is a novel AR antagonist with demonstrated anti-tumour activity in preclinical models and patients with CRPC. To define its anti-cancer effects and features of its recurrent/resistant tumour, we assessed dose-dependent activity of MDV3100 in vivo, and set out to establish MDV3100 resistant cell lines and tumors to characterize its resistant phenotype. Methods. Androgen sensitive human prostate cancer LNCaP cells were inoculated into male athymic nude mice, and when tumour volume reached 150mm3 and serum PSA was 50ng/ml, mice were castrated. When serum PSA levels returned to pre-castrate level, mice were randomly divided into 4 groups of 1, 10 and 50mg/kg of MDV3100 and vehicle treatment groups. Tumour volume and serum PSA were followed weekly. MDV3100 recurrent tumours were harvested and re-cultured in vitro in the presence of MDV3100, or re-implanted into castrated male nude mice treated daily with 10mg/kg of MDV3100. Established cell lines were characterized for response of androgen and MDV3100, and AR and prostate specific antigen (PSA) expressions in vitro. Results. Serum PSA declined -60.8% at 2 weeks and -88.0% at 5 weeks from baseline in 10 and 50mg/kg of MDV3100, respectively. Vehicle and 1mg/kg of MDV3100 did not decrease serum PSA levels. Time to PSA progression from baseline was 6 and 12 weeks at 10 and 50mg/kg MDV3100, respectively. While high doses (50mg/kg) of MDV3100 resulted in the most anti-tumour effect, there were no complete responses and 90% of tumours eventually recurred within 10 weeks’ of treatment. Fifteen cell-lines derived from 7 animals in the high dose group and 3 cell-lines from the animal allografts have been generated to date. Eleven of 12 cell lines showed resistance against 10uM of MDV3100, as proliferation rates were suppressed by a mean of 19% (range, 64.4-98.9%) compared to 50.7% in parental LNCaP cells. Eleven of 12 lines expressed AR while two were PSA negative. Conclusions. While dose-dependent anti-tumour effects of MDV3100 was seen in castrate-resistant LNCaP tumors in vivo, all tumor eventually progressed. Generated MDV3100 resistant cell lines and xenografts were characterized as AR(+)/PSA(+), AR(+)/PSA(−), or AR(−)/PSA(−) and may be useful for modelling resistant phenotypes of MDV3100 in patients. Further characterization is warranted. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1595. doi:10.1158/1538-7445.AM2011-1595