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Pharmacologic inhibition of Jak2-Stat5 signaling By Jak2 inhibitor AZD1480 potently suppresses growth of both primary and castrate-resistant prostate cancer. Clin Cancer Res 2013 Oct 15;19(20):5658-74

Date

08/15/2013

Pubmed ID

23942095

Pubmed Central ID

PMC6021137

DOI

10.1158/1078-0432.CCR-13-0422

Scopus ID

2-s2.0-84886392415   30 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.

Author List

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 P, Gomella L, Huszar D, Nevalainen MT

Author

Marja T. Nevalainen MD, PhD Assistant Dean, Professor in the Pathology department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Aged
Animals
Antineoplastic Agents
Apoptosis
Cell Line, Tumor
Cell Survival
Disease Models, Animal
Humans
Janus Kinase 2
Male
Mice
Middle Aged
Neoplasm Grading
Neoplasm Metastasis
Neoplasm Staging
Orchiectomy
Phosphorylation
Prostatic Neoplasms
Protein Binding
Protein Multimerization
Protein Transport
Pyrazoles
Pyrimidines
Receptors, Androgen
STAT3 Transcription Factor
STAT5 Transcription Factor
Signal Transduction
Transcriptional Activation
Tumor Burden
Xenograft Model Antitumor Assays
jenkins-FCD Prod-400 0f9a74600e4e79798f8fa6f545ea115f3dd948b2