Inhibition of STAT3 with the generation 2.5 antisense oligonucleotide, AZD9150, decreases neuroblastoma tumorigenicity and increases chemosensitivity

Veronica Veschi, Veronica Veschi, Seiichi Odate, Norris Lam, Richard Woessner, Carol J. Thiele, Shuang Yan

Research output: Contribution to journalArticlepeer-review

24 Citations (Scopus)

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.
Original languageEnglish
Pages (from-to)1771-1784
Number of pages14
JournalClinical Cancer Research
Volume23
Publication statusPublished - 2017

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

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