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.