Inhibition of STAT3 with the generation 2.5 antisense oligonucleotide, AZD9150, decreases neuroblastoma tumorigenicity and increases chemosensitivity
Menée sur des lignées cellulaires de neuroblastome et à l'aide de xénogreffes sur des modèles murins, cette étude suggère l'intérêt thérapeutique de développer des inhibiteurs de STAT3 en combinaison avec une chimiothérapie à base de cisplatine
Purpose:Neuroblastoma (NB) is a pediatric tumor of peripheral sympathoadrenal neuroblasts. The long-term event-free survival of children with high-risk NB 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 NB. Experimental Design:To evaluate the biologic consequences of specific targeting of STAT3 in NB, we assessed the effect of tetracycline (Tet)-inducible STAT3 shRNA and the generation 2.5 antisense oligonucleotide AZD9150 which targets STAT3 in 3 representative NB 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 re-implanted into mice there was a significant decrease in secondary tumors in the mice receiving AZD9150-treated tumor cells compared to the mice receiving ntASO-treated tumor cells. This indicates that inhibition of STAT3 decreases the tumor-initiating potential of NB cells. Furthermore, inhibition of STAT3 significantly increased NB 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 NB.