Neuroblastoma is the most deadly extra-cranial solid childhood tumor. Despite advanced therapies, over 60% of high-risk NB patients have aggressive tumors spreading to bone and bone marrow and die of metastasis-related disease. IL-6 promotes the growth and survival of metastatic NB cells via activation of STAT3 in the BM and is an independent poor-prognosis marker in tumors from high-risk NB patients. This suggests that blockade of IL6/JAK/STAT3 signaling may represent a promising therapeutic strategy. We tested the anti-tumor effect of inhibition IL6/JAK/STAT3 pathway by the JAK1/2 inhibitor AZD1480, which is in Phase II clinical trials in adult tumors, in three highly metastatic pediatric tumor types (Neuroblastoma, Ewing sarcoma and rhabdomyosarcoma). AZD1480 (0.5uM) significantly blocked IL-6-induced P-STAT3-Tyr705 in all tumor types tested. AZD1480 decreased cell viability in the 6 NB, 5 RMS and 2 EWS cell lines tested (median IC50 1.17uM, ranging from 0.42-5.1uM). AZD1480 induced cell growth inhibition, G2 arrest and apoptosis in vitro. Moreover, AZD1480 inhibited the expression of identified direct STAT3 targets such as cell cycle regulators CyclinD2, CyclinD3 and CDC25A, antiapoptotic proteins Bcl-2 and Survivin, metastasis-related protein TIMP-1 and c-myc consistent with its repression of cell growth, induction of G2 arrest and apoptosis. In in vivo Neuroblastoma xenograft models, AZD1480 suppressed growth of SY5Y and KCNR xenografts and increased survival of mice bearing KCNR xenografts (P=0.0001) and SY5Y xenografts (P=0.02). Altogether, these data suggest the clinical blockade of IL6/JAK/STAT3 signaling by AZD1480 may represent a promising new therapy in NB and other pediatric tumors. We thank Dennis Huszar and AstraZeneca for the AZD1480 and helpful discussions. Key words: neuroblastoma, JAK2, STAT3, IL-6, targeted therapy

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1440. doi:1538-7445.AM2012-1440

©2012 American Association for Cancer Research
2012