Abstract 4699: Preclinical activity of the AKT inhibitor AZD5363 in PTEN-deficient mouse models of prostate cancer

Abstract

Abstract Increased phosphoinositide 3-kinase (PI3K) pathway activity is commonly observed in human prostate cancer and constitutes a potential target for therapeutic intervention. AZD5363 is a potent pan-AKT kinase inhibitor that is currently being investigated in phase 1 and 2 clinical trials in solid cancers including prostate. AZD5363 has demonstrated strong anti-tumor activity against human prostate cancer cells in vitro and in vivo. Genetically engineered mouse models mimic the genetic and biological evolution of human prostate cancer and address deficiencies encountered with xenograft models. In the present study, we examined in vivo target validation, pharmacodynamics, and antitumor responses of AZD5363 monotherapy in a PTEN-deficient mouse model of prostate cancer, and show the survival benefit in an advanced prostate cancer model driven by PTEN/P53 inactivation. Downstream targets of AKT were inhibited in a dose-dependent manner and activity of AZD5363 at was observed up to 8 hours after a single dose of 100 mg/kg. Tumor cell proliferation and the induction of apoptosis paralleled the activity of AZD5363. Compared to vehicle treated mice, chronic administration of AZD5363 at 100 mg/kg B.I.D. 5 times per week for 4 weeks inhibited growth of castration-naïve and castration-resistant prostate cancers by 15.9% ±4.3 and 20.2% ±4.4, respectively. Inhibition of S6 phosphorylation was effectively maintained the after chronic administration of AZD5363 and was accompanied by decreased proliferation rates and increase in apoptosis. Furthermore, in a long-term survival study of PTEN/P53 double knockout mice, treatment with AZD5363 significantly improved survival rates from 24 to 37 days, P<0.011. In conclusion, our findings indicate that AZD5363 is effective against autochthonous models of mouse prostate cancer and support further investigation of the AKT inhibitor for the treatment of PTEN-deficient prostate cancer. Citation Format: Marco A. De Velasco, Yuji Hatanaka, Yurie Kura, Emiko Fukushima, Naomi Ando, Barry R. Davies, Yutaka Yamamoto, Takashi Oki, Nobutaka Shimizu, Kazuhiro Yoshimura, Masahiro Nozawa, Kazuhiro Yoshikawa, Kazuto Nishio, Hirotsugu Uemura. Preclinical activity of the AKT inhibitor AZD5363 in PTEN-deficient mouse models of prostate cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4699. doi:10.1158/1538-7445.AM2015-4699