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|Ref Type||Journal Article|
|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|
|Date||2013 Apr 1|
|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.|
|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|
|Gene||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 Sulfate||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|