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• W2317828515 abstract "Background: Neuroblastoma originates from neural crest cells and is one of the most common and deadly tumors of childhood. The majority of tumors develop therapy resistance with fatal clinical outcome despite intensive multimodal therapy. The Hedgehog (HH) signaling pathway is fundamental in embryonic development, controlling cell fate and proliferation. Activation of HH signaling is involved in several cancers, among them pediatric cancers. Studies have revealed that human neuroblastoma cells express high levels of proteins involved in HH signaling. GANT61 was recently identified as an inhibitor of GLI1 and GLI2, important transcription factors in the HH signaling pathway. The aim of this study was to investigate the impact of antagonists of HH signaling in neuroblastoma through characterization of the effects of small molecule inhibitors of the HH pathway, in vitro and in vivo. Methods: Cytotoxic activity of HH inhibitors was studied in cell viability and clonogenic assays. The molecular mechanisms were characterized using cell- and molecular biology techniques. Xenograft studies in mice were performed to validate the therapeutic effects and toxicity in vivo. Results: The cytotoxicity of different HH inhibitors (cyclopamine, SANT1 and GANT61) was evaluated in a panel of human neuroblastoma cell lines. GANT61 was the most potent drug tested with IC50 values in the range of 5.8 - 13 µM after 72h incubation. Expression of GLI1 significantly correlated to the log IC50 for GANT61 (R2=0.88), the higher the expression of GLI1 the lower the amount of GANT61 was required to inhibit cellular growth. We also saw an inverse correlation with MYCN (R2=−0.88). When measured with a GLI-dependent luciferase reporter plasmid, the GLI activity was decreased with 36% to 80% after GANT61 treatment (10 µM, 48h) depending on cell line. Investigation of cell cycle regulation and cell death demonstrated that GANT61 inhibited proliferation and induced apoptosis. siRNA experiments revealed that knockdown of GLI1 reduced proliferation more potently than GLI2, GLI3 and SMO inhibition. GANT61 significantly inhibited tumor growth in neuroblastoma xenografts in nude NMRI nu/nu mice without causing any sign of toxicity. Conclusions: These results suggest that inhibitors of the HH signaling pathway such as GANT61 may constitute a novel option for treatment to patient with high-risk neuroblastoma without MYCN-amplification. 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 4725. doi:1538-7445.AM2012-4725" @default.
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• W2317828515 date "2012-04-15" @default.
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• W2317828515 title "Abstract 4725: Inhibition of the Hedgehog signaling pathway - a new target in treatment for children with neuroblastoma" @default.
• W2317828515 doi "https://doi.org/10.1158/1538-7445.am2012-4725" @default.
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