Inhibition of STAT3 with the Generation 2.5 Antisense Oligonucleotide, AZD9150, Decreases Neuroblastoma Tumorigenicity and Increases Chemosensitivity

S Odate, V Veschi, S Yan, N Lam, R Woessner… - Clinical Cancer …, 2017 - AACR
S Odate, V Veschi, S Yan, N Lam, R Woessner, CJ Thiele
Clinical Cancer Research, 2017AACR
Purpose: Neuroblastoma is a pediatric tumor of peripheral sympathoadrenal neuroblasts.
The long-term event-free survival of children with high-risk neuroblastoma is still poor
despite the improvements with current multimodality treatment protocols. Activated
JAK/STAT3 pathway plays an important role in many human cancers, suggesting that
targeting STAT3 is a promising strategy for treating high-risk neuroblastoma. Experimental
Design: To evaluate the biologic consequences of specific targeting of STAT3 in …
Abstract
Purpose: Neuroblastoma is a pediatric tumor of peripheral sympathoadrenal neuroblasts. The long-term event-free survival of children with high-risk neuroblastoma is still poor despite the improvements with current multimodality treatment protocols. Activated JAK/STAT3 pathway plays an important role in many human cancers, suggesting that targeting STAT3 is a promising strategy for treating high-risk neuroblastoma.
Experimental Design: To evaluate the biologic consequences of specific targeting of STAT3 in neuroblastoma, we assessed the effect of tetracycline (Tet)-inducible STAT3 shRNA and the generation 2.5 antisense oligonucleotide AZD9150 which targets STAT3 in three representative neuroblastoma cell line models (AS, NGP, and IMR32).
Results: Our data indicated that Tet-inducible STAT3 shRNA and AZD9150 inhibited endogenous STAT3 and STAT3 target genes. Tet-inducible STAT3 shRNA and AZD9150 decreased cell growth and tumorigenicity. In vivo, STAT3 inhibition by Tet-inducible STAT3 shRNA or AZD9150 alone had little effect on growth of established tumors. However, when treated xenograft tumor cells were reimplanted into mice, there was a significant decrease in secondary tumors in the mice receiving AZD9150-treated tumor cells compared with the mice receiving ntASO-treated tumor cells. This indicates that inhibition of STAT3 decreases the tumor-initiating potential of neuroblastoma cells. Furthermore, inhibition of STAT3 significantly increased neuroblastoma cell sensitivity to cisplatin and decreased tumor growth and increased the survival of tumor-bearing mice in vivo.
Conclusions: Our study supports the development of strategies targeting STAT3 inhibition in combination with conventional chemotherapy for patients with high-risk neuroblastoma. Clin Cancer Res; 23(7); 1771–84. ©2016 AACR.
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