Activation of signal transducer and activator of transcription (STAT) 3 via the interleukin 6 (IL-6)/IL-6R/Janus kinase (JAK) signaling axis is a feature common in patients with advanced human prostate cancer and has been associated with poor prognosis. STAT3 can promote CRPC growth by activating the androgen receptor signaling pathway. It can also promote survival by modulating tumor cell proliferation, epithelial to mesenchymal transition, angiogenesis and immune response. However, recent preclinical data suggests that STAT3 may also act as a tumor suppressor in PTEN-deficient prostate cancer. In this study, we investigated the effectiveness of AZD1480, a potent JAK1/2 inhibitor, in genetically engineered mouse models of prostate cancer driven by the loss of PTEN and PTEN/P53. In vivo pharmacodynamic studies using conditional PTEN-deficient mice demonstrated that AZD1480 strongly inhibited STAT3 phosphorylation. Moreover, AZD1480 monotherapy in PTEN-deficient mice harboring castration-naïve or castration-resistant prostate tumors resulted in tumor growth reductions of 24.8%, P<0.001 and 15.8%, P<0.001, respectively, compared to vehicle treated control mice. Mice treated with AZD1480 also exhibited reduced levels of tumor cell proliferation and microvessel density, and increased apoptosis compared to controls. Clinically relevant outcomes were evaluated in a late-stage model of prostate cancer driven by the conditional inactivation of PTEN and P53. In this model, PTEN/P53 double knockout mice with established tumors were randomized to vehicle or AZD1480 treatment groups. Mice treated with AZD1480 demonstrated a modest but statistically significant improvement in overall survival compared to control mice, median time 20 days vs. 27 days, P = 0.03, respectively. Additionally, the metastatic tumor incidence decreased from 46.6% (7/15) in control mice to 20% (3/15) in AZD1480-treated mice. Our findings provide preclinical evidence supporting the potential use of Jak1/2 inhibitors for the targeted therapy of human prostate cancer.

Citation Format: Marco A. De Velasco, Yurie Kura, Naomi Ando, Emiko Fukushima, Yuji Hatanaka, Takashi Oki, Kazuhiro Yoshimura, Masahiro Nozawa, Barry R. Davies, Dennis Huszdar, Kazuhiro Yoshikawa, Kazuto Nishio, Hirotsugu Uemura. The Jak1/2 inhibitor AZD1480 suppresses tumor growth and metastasis in genetically engineered mouse models of PTEN-deficient prostate cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3864.

©2016 American Association for Cancer Research.
2016
American Association for Cancer Research.