title: Inhibition ofSTAT3with the Generation 2.5 Antisense Oligonucleotide, AZD9150, Decreases Neuroblastoma Tumorigenicity and Increases Chemosensitivity.
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 micein vivoConclusions: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.
authors: Cell & Molecular Biology Section, Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland.
authors: Seiichi
authors: S
authors: Odate
authors: Cell & Molecular Biology Section, Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland.
authors: Veronica
authors: V
authors: Veschi
authors: Cell & Molecular Biology Section, Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland.
authors: Shuang
authors: S
authors: Yan
authors: Cell & Molecular Biology Section, Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland.
authors: Norris
authors: N
authors: Lam
authors: Cancer Bioscience Drug Discovery, AstraZeneca Pharmaceuticals, Waltham, Massachusetts.
authors: Richard
authors: R
authors: Woessner
authors: Cell & Molecular Biology Section, Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland. thielec@mail.nih.gov.
authors: Carol J
authors: CJ
authors: Thiele
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols; D017209:Apoptosis / Q000187:drug effects; D063646:Carcinogenesis / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002945:Cisplatin / Q000008:administration & dosage; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D051379:Mice; D009447:Neuroblastoma / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D009841:Oligonucleotides / Q000008:administration & dosage*; D016376:Oligonucleotides, Antisense / Q000008:administration & dosage*; D050796:STAT3 Transcription Factor / Q000235:genetics*; D023041:Xenograft Model Antitumor Assays
chemical_list: D009841:Oligonucleotides; D016376:Oligonucleotides, Antisense; D050796:STAT3 Transcription Factor; C000610954:danvatirsen; D002945:Cisplatin