title: Targeting the Hedgehog signaling pathway in cancer: beyond Smoothened.
abstract: An essential role for Hedgehog (Hh) signaling in human cancer has been established beyond doubt. At present, targeting Hh signaling has mainly been investigated with SMO inhibitors. Unfortunately, resistance against currently used SMO inhibitors has already been observed in basal cell carcinoma (BCC) patients. Therefore, the use of Hh inhibitors targeting the signaling cascade more downstream of SMO could represent a more promising strategy. Furthermore, besides the classical canonical way of Hh signaling activation, non-canonical activation of the GLI transcription factors by multiple important signaling pathways (e.g. MAPK, PI3K, TGFβ) has also been described, pinpointing the importance of targeting the transcription factors GLI1/2. The most promising agent in this context is probably the GLI1/2 inhibitor GANT61 which has been investigated preclinically in numerous tumor types in the last few years. In this review, the emerging role of Hh signaling in cancer is critically evaluated focusing on the potential of targeting Hh signaling more downstream of SMO, i.e. at the level of the GLI transcription factors. Furthermore, the working mechanism and therapeutic potential of the most extensively studied GLI inhibitor in human cancer, i.e. GANT61, is discussed in detail. In conclusion, GANT61 appears to be highly effective against human cancer cells and in xenograft mouse models, targeting almost all of the classical hallmarks of cancer and could hence represent a promising treatment option for human cancer.
authors.affiliation: University of Leuven (KU Leuven), Department of Oncology, Laboratory of Experimental Radiotherapy, Leuven, Belgium.
authors.forename: Annelies
authors.initials: A
authors.lastname: Gonnissen
authors.affiliation: University of Leuven (KU Leuven), Department of Oncology, Laboratory of Experimental Radiotherapy, Leuven, Belgium.
authors.forename: Sofie
authors.initials: S
authors.lastname: Isebaert
authors.affiliation: University of Leuven (KU Leuven), Department of Oncology, Laboratory of Experimental Radiotherapy, Leuven, Belgium.|University Hospitals Leuven, Department of Radiation Oncology, Leuven, Belgium.
authors.forename: Karin
authors.initials: K
authors.lastname: Haustermans
mesh_terms: D000818:Animals; D053823:Hedgehog Proteins / Q000378:metabolism*; D006801:Humans; D058990:Molecular Targeted Therapy; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism*; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D053823:Hedgehog Proteins; D043562:Receptors, G-Protein-Coupled
keywords: DNA repair; GANT61; GLI transcription factors; Hedgehog pathway; apoptosis