Matthias Busemann

Abstract 1321: Castration-resistant prostate cancer: BAY 1024767 blocks function of mutated androgen receptor.

Proceedings: AACR 104th Annual Meeting 2013; Apr 6-10, 2013; Washington, DC Analysis of biopsies from prostate cancer metastases and of circulating tumor cells shows that androgen receptor (AR) mutations are often found in patients developing resistance to antiandrogen therapy, i.e. at the castration-resistant prostate cancer (CRPC) stage. Here we report on preclinical studies with a novel androgen receptor suppressor compound BAY 1024767 that exhibits strong antagonism for wild-type and mutated AR, both in vitro and in vivo. Mutations located in the AR ligand-binding domain (LBD) and potentially involved in the resistance to the standard of care bicalutamide were generated and tested in cell-based transactivation assays, using 0.1 nM R1881 for stimulation. Bicalutamide showed reduced antagonistic activity for AR E709Y and no antagonism up to 10 μM for AR W741C. In comparison, BAY 1024767 exhibited strong antagonism for these mutants. Another mechanism leading to CRPC is the elevation of intratumoral androgen levels. To mimick this situation, the transactivation assays were performed at a higher (1 and 10 nM R1881) androgen concentration. Bicalutamide, and also the novel antiandrogen MDV3100, showed much reduced antagonism for wild-type and W741C or E709Y mutant AR. Conversely, antagonism was still observed for BAY 1024767, especially at 1 nM R1881. The KuCaP-1 model, which is derived from a CRPC patient and harbors the W741C mutation, was obtained from the group of O. Ogawa (Kyoto University). Mice bearing the KuCaP-1 xenograft subcutaneously were treated with bicalutamide (60 mg/kg, PO, qdx20) or BAY 1024767 (50 mg/kg, PO, q2dx10). No effect on tumor growth was observed with bicalutamide (T/C=103%) whereas BAY 1024767 was able to inhibit tumor growth with a T/C of 36% on day 54 post-implantation. In another study we found that MDV 3100 (100 mg/kg, PO) and abiraterone acetate (200 mg/kg, PO) were inactive in the KuCaP-1 model (100% and 73% T/C, respectively). Citation Format: Bernard Haendler, Tatsuo Sugawara, Pascale Lejeune, Silke Koehr, Hortensia Faus, Matthias Busemann, Arwed Cleve, Ulrich Luecking, Franz von Nussbaum, Michael Brands, Dominik Mumberg. Castration-resistant prostate cancer: BAY 1024767 blocks function of mutated androgen receptor. [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 1321. doi:10.1158/1538-7445.AM2013-1321