Pharmacologic inhibition of Jak2-Stat5 signaling by Jak2 inhibitor AZD1480 potently suppresses growth of both primary and castrate-resistant prostate cancer

Lei Gu, Zhiyong Liao, David T. Hoang, Ayush Dagvadorj, Shilpa Gupta, Shauna Blackmon, Elyse Ellsworth, Pooja Talati, Benjamin Leiby, Michael Zinda, Costas D. Lallas, Edouard J. Trabulsi, Peter McCue, Leonard Gomella, Dennis Huszar, Marja T. Nevalainen

Research output: Contribution to journalArticlepeer-review

36 Scopus citations

Abstract

Purpose: Progression of prostate cancer to the lethal castrate-resistant stage coincides with loss of responsiveness to androgen deprivation and requires development of novel therapies. We previously provided proof-of-concept that Stat5a/b is a therapeutic target protein for prostate cancer. Here, we show that pharmacologic targeting of Jak2-dependent Stat5a/b signaling by the Jak2 inhibitor AZD1480 blocks castrate-resistant growth of prostate cancer. Experimental Design: Efficacy of AZD1480 in disrupting Jak2-Stat5a/b signaling and decreasing prostate cancer cell viability was evaluated in prostate cancer cells. A unique prostate cancer xenograft mouse model (CWR22Pc), which mimics prostate cancer clinical progression in patients, was used to assess in vivo responsiveness of primary and castrate-resistant prostate cancer (CRPC) to AZD1480. Patient-derived clinical prostate cancers, grown ex vivo in organ explant cultures, were tested for responsiveness to AZD1480. Results: AZD1480 robustly inhibited Stat5a/b phosphorylation, dimerization, nuclear translocation, DNA binding, and transcriptional activity in prostate cancer cells. AZD1480 reduced prostate cancer cell viability sustained by Jak2-Stat5a/b signaling through induction of apoptosis, which was rescued by constitutively active Stat5a/b. In mice, pharmacologic targeting of Stat5a/b by AZD1480 potently blocked growth of primary androgen-dependent as well as recurrent castrate-resistant CWR22Pc xenograft tumors, and prolonged survival of tumor-bearing mice versus vehicle or docetaxel-treated mice. Finally, nine of 12 clinical prostate cancers responded to AZD1480 by extensive apoptotic epithelial cell loss, concurrent with reduced levels of nuclear Stat5a/b. Conclusions: We report the first evidence for efficacy of pharmacologic targeting of Stat5a/b as a strategy to inhibit castrate-resistant growth of prostate cancer, supporting further clinical development of Stat5a/b inhibitors as therapy for advanced prostate cancer.

Original languageEnglish (US)
Pages (from-to)5658-5674
Number of pages17
JournalClinical Cancer Research
Volume19
Issue number20
DOIs
StatePublished - Oct 15 2013

Fingerprint Dive into the research topics of 'Pharmacologic inhibition of Jak2-Stat5 signaling by Jak2 inhibitor AZD1480 potently suppresses growth of both primary and castrate-resistant prostate cancer'. Together they form a unique fingerprint.

Cite this