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

Authors

• 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

Publication/Presentation Date

10-15-2013

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.

Volume

19

Issue

20

First Page

5658

Last Page

5674

ISSN

1557-3265

Published In/Presented At

Gu, L., Liao, Z., Hoang, D. T., Dagvadorj, A., Gupta, S., Blackmon, S., Ellsworth, E., Talati, P., Leiby, B., Zinda, M., Lallas, C. D., Trabulsi, E. J., McCue, P., Gomella, L., Huszar, D., & Nevalainen, M. T. (2013). Pharmacologic inhibition of Jak2-Stat5 signaling By Jak2 inhibitor AZD1480 potently suppresses growth of both primary and castrate-resistant prostate cancer. Clinical cancer research : an official journal of the American Association for Cancer Research, 19(20), 5658–5674. https://doi.org/10.1158/1078-0432.CCR-13-0422

Disciplines

Business Administration, Management, and Operations | Health and Medical Administration | Management Sciences and Quantitative Methods

PubMedID

23942095

Department(s)

Administration and Leadership

Document Type

Article