Abstract 1850: Evaluation of Pim-1 kinase inhibition in a preclinical model of mouse prostate cancer

Abstract

Abstract Pim-1 is a serine/threonine kinase that is in involved in the transcription of genes that regulate apoptosis and cell cycle progression. Pim-1 has been shown to be overexpressed in a variety of cancers and has been implicated in human prostate tumorigenesis. The aim of our study was to clarify the role of Pim-1 during the prostate tumorigenesis and determine its potential as a molecular target for therapy. To accomplish this goal, we carried out a series of experiments using a genetically engineered mouse model of prostate cancer driven by the conditional inactivation of PTEN. High levels of Pim-1 were observed during the early stages of the tumorigenesis process which decreased as tumors progressed. Expression of Pim-1 was localized in the nucleus and cytoplasm of prostatic intraepithelial neoplasia (PIN), well-differentiated, and moderately-differentiated tumors. In poorly-differentiated tumors, Pim-1expression was heterogeneously expressed at lower levels and was predominantly localized to the cytoplasm of cancer cells. Levels of Pim-1 expression were increased in tumors from mice after surgical castration. To evaluate the therapeutic potential of Pim-1as a target for prostate cancer, we tested the antitumor effects of AZD1208, a highly potent Pim kinase inhibitor, on a panel of cell lines derived from castration-naïve and castration-resistant mouse prostate cancer. AZD1208 inhibited the tumor cell growth of several cell lines and demonstrated higher sensitivity to those derived from castration resistant tumors. In vivo, drug intervention studies show that treatment with AZD1208 reduced tumor growth of castration-naïve and castration-resistant prostate tumors by 12.1 (P = 0.162) and 24.3% (P<0.001), respectively. These findings provide further support for a role of Pim-1 during prostate tumorigenesis and could thus serve as a rational target for the development of novel combination strategies. Citation Format: Marco A. De Velasco, Takashi Oki, Yurie Kura, Naomi Ando, Emiko Fukushima, Barry R. Davies, Dennis Huszar, Yutaka Yamamoto, Yuji Hatanaka, Nobutaka Shimizu, Kazuhiro Yoshimura, Masahiro Nozawa, Kazuhiro Yoshikawa, Kazuto Nishio, Hirotsugu Uemura. Evaluation of Pim-1 kinase inhibition in a preclinical model of mouse 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 1850. doi:10.1158/1538-7445.AM2015-1850