PHARMACOLOGICAL INHIBITION OF JAK2-STAT5 SIGNALING BY JAK2 INHIBITOR AZD1480 POTENTLY SUPPRESSES GROWTH OF BOTH PRIMARY AND CASTRATE-RESISTANT PROSTATE CANCER
Nevalainen MT, Gu L, Liao Z, Hoang DT, Dagvadorj A, Gupta S, Blackmon S, Ellsworth E, Talati P, Leiby B, Zinda M, Lallas CD, Trabulsi EJ, McCue PA, Gomella LG, Huszar D. Clin Cancer Res. 2013 Aug 13. [Epub ahead of print]

Source

Dept. of Cancer Biology, Medical Oncology, Urology, Thomas Jefferson University.

Abstract

PURPOSE:

Progression of prostate cancer (PC) to the lethal castrate-resistant (CR) 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 PC. Here we demonstrate that pharmacological targeting of Jak2-dependent Stat5a/b signaling by the Jak2 inhibitor AZD1480 blocks CR growth of PC.

EXPERIMENTAL DESIGN:

Efficacy of AZD1480 in disrupting Jak2-Stat5a/b signaling and decreasing PC cell viability was evaluated in PC cells. A unique PC xenograft mouse model (CWR22Pc), which mimics PC clinical progression in patients, was used to assess in vivo responsiveness of primary and CR PC to AZD1480. Patient-derived clinical PCs, 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 PC cells. AZD1480 reduced PC cell viability sustained by Jak2-Stat5a/b signaling through induction of apoptosis, which was rescued by constitutively active Stat5a/b. In mice, pharmacological targeting of Stat5a/b by AZD1480 potently blocked growth of primary androgen-dependent as well as recurrent CR CWR22Pc xenograft tumors, and prolonged survival of tumor-bearing mice vs. vehicle or docetaxel-treated mice. Finally, 9 of 13 clinical PCs 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 pharmacological targeting of Stat5a/b as a strategy to inhibit CR growth of PC, supporting further clinical development of Stat5a/b inhibitors as therapy for advanced PC.