Abstract
The IL-6/JAK/STAT pathway is a key signal transduction pathway implicated in the pathogenesis of many human cancers, suggesting that kinase inhibitors targeting JAK/STAT3 may have a broad spectrum of antitumor activity. AZD1480, a pharmacological JAK1/2 inhibitor, exhibits anti-tumor potency in multiple adult malignancies. To evaluate the efficacy of inhibition of JAK/STAT3 signal transduction pathway we assessed the activity of AZD1480 in pediatric malignancies using preclinical models of three highly malignant pediatric solid tumors: neuroblastoma (NB), rhabdomyosarcoma (RMS) and the Ewing Sarcoma Family Tumors (ESFT). In this study, we employed panels of biomedical and biological experiments to evaluate the in vitro and in vivo activity of AZD1480 in NB, RMS and ESFT. Our data indicate that AZD1480 blocks endogenous as well as IL-6 induced STAT3 activation. AZD1480 decreases cell viability in 7/7NB, 7/7RMS and 2/2 ESFT cell lines (median EC50 is 1.5 μM, ranging from 0.36-5.37 μM). AZD1480 induces cell growth inhibition and caspase-dependent apoptosis in vitro and decreases expression of STAT3 target genes, including cell cycle regulators CyclinD1, 3 and CDC25A, anti-apoptotic genes Bcl-2 and survivin, the metastasis-related factor TIMP-1 and c-Myc. In vivo studies showed AZD1480 significantly decreased tumor growth and prolonged overall survival in tumor-bearing mice. Tumors from AZD1480-treated mice showed inhibition of activated STAT3 as well as decreased expression of STAT3 downstream targets. Our study provides strong evidence of the anti-tumor growth potency of JAK inhibitor AZD1480 in pediatric solid tumors, providing proof-of principle that inhibition of the JAK/STAT3 signal transduction could be a promising therapeutic target for high-risk pediatric solid tumors.
Highlights
Since the 1950s, the overall survival (OS) of pediatric cancer patients has increased from almost 0 to 80%
To test whether inhibition of the Janus kinase (JAK)/STAT3 pathway would affect the growth of pediatric solid tumors, we evaluated the anti-tumor activity of AZD1480, an ATP competitive inhibitor of JAK1 and JAK2, which has been shown to decrease the growth of adult tumors in several pre-clinical models [24,25,26,27,28]
We found that AZD1480-mediated inhibition of the JAK/ STAT3 pathway resulted in in vitro and in vivo suppression of tumor growth in neuroblastoma, rhabdomyosarcoma and Ewing sarcoma
Summary
Since the 1950s, the overall survival (OS) of pediatric cancer patients has increased from almost 0 to 80%. Treatment of aggressive, high-risk neuroblastoma (NB), rhabdomyosarcoma (RMS) and Ewing sarcoma family tumors (ESFT) has remained a challenge. NB is the most common extra-cranial solid malignancy [1], RMS is the most common sarcoma and ESFT is the second most common bone tumor of childhood [1,2]. Low- and intermediated-risk NB, RMS and ESFT are mostly curable, and have excellent long-term survival rates with standard therapies. Patients with high-risk aggressive NB, RMS and ESFT have a dismal outcome. Despite the current intensive therapy, the long-term eventfree survival of high-risk NB is less than 40% [1,3], and the long-term OS in high-risk RMS and ESFT is only 30% and 39% [4,5,6,7], respectively. New treatment strategies are urgently needed to improve the outcomes of patients with these malignancies
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