Reference Detail

Ref Type Journal Article
PMID (22949014)
Authors Wickstrom M, Dyberg C, Shimokawa T, Milosevic J, Baryawno N, Fuskevag OM, Larsson R, Kogner P, Zaphiropoulos PG, Johnsen JI
Title Targeting the hedgehog signal transduction pathway at the level of GLI inhibits neuroblastoma cell growth in vitro and in vivo.
Journal International journal of cancer
Vol 132
Issue 7
Date 2013 Apr 1
URL
Abstract Text Hedgehog (HH) signaling is an important regulator of embryogenesis that has been associated with the development of several types of cancer. HH signaling is characterized by Smoothened (SMO)-dependent activation of the GLI transcription factors, which regulate the expression of critical developmental genes. Neuroblastoma, an embryonal tumor of the sympathetic nervous system, was recently shown to express high levels of key molecules in this signaling cascade. Using compounds blocking SMO (cyclopamine and SANT1) or GLI1/GLI2 (GANT61) activity revealed that inhibition of HH signaling at the level of GLI was most effective in reducing neuroblastoma growth. GANT61 sensitivity positively correlated to GLI1 and negatively to MYCN expression in the neuroblastoma cell lines tested. GANT61 downregulated GLI1, c-MYC, MYCN and Cyclin D1 expression and induced apoptosis of neuroblastoma cells. The effects produced by GANT61 were mimicked by GLI knockdown but not by SMO knockdown. Furthermore, GANT61 enhanced the effects of chemotherapeutic drugs used in the treatment of neuroblastoma in an additive or synergistic manner and reduced the growth of established neuroblastoma xenografts in nude mice. Taken together this study suggests that inhibition of HH signaling is a highly relevant therapeutic target for high-risk neuroblastoma lacking MYCN amplification and should be considered for clinical testing.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
Unknown unknown neuroblastoma not applicable Doxorubicin + GANT61 Preclinical Actionable In a preclinical study, GANT61 and Adriamycin (doxorubicin) worked synergistically to inhibit growth of neuroblastoma cells in culture (PMID: 22949014). 22949014
Unknown unknown neuroblastoma not applicable GANT61 + Vincristine Preclinical Actionable In a preclinical study, GANT61 and Oncovin (vincristine) worked synergistically to inhibit growth of neuroblastoma cells in culture (PMID: 22949014). 22949014
Unknown unknown neuroblastoma not applicable GANT61 Preclinical - Cell line xenograft Actionable In a preclinical study, GANT61 induced apoptosis and decreased growth of neuroblastoma cells in culture, and inhibited tumor growth in neuroblastoma cell line xenograft models (PMID: 22949014). 22949014