Abstract 4825: Targeting PIM and AKT kinases impairs tumor growth and improves overall survival in a murine model of advanced castration-resistant prostate cancer

Abstract

Abstract Background: Castration-resistant prostate cancer (CRPC) is an incurable disease with few treatment options, thus novel treatment strategies are required. PIM serine/threonine kinases (PIM-1, PIM-2, and PIM-3) are overexpressed in various cancers and are correlated with human prostate cancer progression. We previously evaluated the antitumor activity of the pan-PIM kinase inhibitor AZD1208 and showed that it could effectively suppress tumor growth in early-stage mouse models of castration-naïve and castration-resistant Pten-deficient prostate cancer. To fully determine the therapeutic potential of PIM inhibition we examined the therapeutic efficacy of AZD1208 in a mouse model of advanced prostate using clinically relevant endpoints. Additionally, since AKT and PIM kinases modulate survival processes by the phosphorylation of common substrates, we also examined the treatment combination with the pan-AKT inhibitor, AZD5363. Methods: PSACre:Ptenflox/flox/Trp53flox/flox double knockout (Pten/P53-DKO) mice bearing palpable tumors with an initial size of 0.5 cm were surgically castrated and randomized to treatments with control vehicle, AZD1208 (60 mg/kg/day), AZD5363 (100 mg/kg/b.i.d) or AZD1208 + AZD5363 upon tumor progression or two weeks after castration, whichever occurred first. Tolerability was assessed by comparing differences in bodyweight and mouse health performance status. Therapeutic efficacy was determined by overall survival and antitumor activity was assessed by comparing tumor growth rates. Results: Treatments appeared to be well tolerated by the mice and no significant differences were noted in bodyweight changes between treatment groups. Median overall survival times were 21, 28, 28 and 35 days for vehicle, AZD1208, AZD5363 and AZD1208+AZD5363 treated mice , respectively, P=0.027. Median time to tumor doubling (1→2 cm) was longer for AZD1208 and AZD1208+AZD5363 treatment groups compared to vehicle or AZD5363, 28, 21, 14 and 14 days, respectively, P=0.005. Conclusions: Treatments with AZD1208 suppressed CRPC growth and improved overall survival times in Pten/P53-DKO mice. Furthermore, targeting both PIM and AKT kinases with combination therapy improved overall survival. This study provides evidence to support further development of therapeutic strategies targeting PIM and AKT for the management of human advanced prostate cancer. Citation Format: Marco A. De Velasco, Yurie Kura, Naomi Ando Ando, Noriko Sato, Barry R. Davies, Masahiro Nozawa, Kazuhiro Yoshimura, Kazuhiro Yoshikawa, Kazuto Nishio, Hirotsugu Uemura. Targeting PIM and AKT kinases impairs tumor growth and improves overall survival in a murine model of advanced castration-resistant prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4825.