5c43cc813b6999d3386b51ec9a822117 pmc_9913695.pdf c9139bd9960655c62bb35b38cfe84900ab044781 pmc_9913695.pdf c35d679ed89301c723e53a003726c021f23704baa2a899835ced73e4d11541a8 pmc_9913695.pdf Title: Targeting the Hedgehog Pathway in Rhabdomyosarcoma Subject: Aberrant activation of the Hedgehog (Hh) signalling pathway is known to play an oncogenic role in a wide range of cancers; in the particular case of rhabdomyosarcoma, this pathway has been demonstrated to be an important player for both oncogenesis and cancer progression. In this review, after a brief description of the pathway and the characteristics of its molecular components, we describe, in detail, the main activation mechanisms that have been found in cancer, including ligand-dependent, ligand-independent and non-canonical activation. In this context, the most studied inhibitors, i.e., SMO inhibitors, have shown encouraging results for the treatment of basal cell carcinoma and medulloblastoma, both tumour types often associated with mutations that lead to the activation of the pathway. Conversely, SMO inhibitors have not fulfilled expectations in tumours—among them sarcomas—mostly associated with ligand-dependent Hh pathway activation. Despite the controversy existing regarding the results obtained with SMO inhibitors in these types of tumours, several compounds have been (or are currently being) evaluated in sarcoma patients. Finally, we discuss some of the reasons that could explain why, in some cases, encouraging preclinical data turned into disappointing results in the clinical setting. Keywords: cancer; paediatric cancer; soft tissue sarcomas; STS; embryonic pathways; Hh pathway; SMO; Sonic; Indian; Desert; PTCH; SUFU; CDO; BOC; GAS1 Author: Patricia Zarzosa, Lia Garcia-Gilabert, Raquel Hladun, Gabriela Guillén, Gabriel Gallo-Oller, Guillem Pons, Julia Sansa-Girona, Miguel F. Segura, Josep Sánchez de Toledo, Lucas Moreno, Soledad Gallego and Josep Roma Creator: LaTeX with hyperref Producer: pdfTeX-1.40.21 CreationDate: Mon Feb 6 10:03:46 2023 CET ModDate: Mon Feb 6 10:09:13 2023 CET Tagged: no UserProperties: no Suspects: no Form: none JavaScript: no Pages: 17 Encrypted: no Page size: 595.276 x 841.89 pts (A4) Page rot: 0 File size: 1146358 bytes Optimized: no PDF version: 1.7 name type encoding emb sub uni object ID ------------------------------------ ----------------- ---------------- --- --- --- --------- GIFXFT+VnURWPalladioL-Bold Type 1 Custom yes yes no 10 0 TKJEDQ+VnURWPalladioL Type 1 Custom yes yes no 15 0 FZFQMM+URWPalladioL-Bold Type 1 Custom yes yes no 19 0 VUJPBU+URWPalladioL-Roma Type 1 Custom yes yes no 24 0 GVXBTJ+URWPalladioL-Ital Type 1 Custom yes yes no 28 0 LCJEVJ+TimesNewRomanPS-BoldItalicMT Type 1C WinAnsi yes yes no 47 0 DPOLGL+PalatinoLinotype,Bold TrueType WinAnsi yes yes no 79 0 DPOLGN+PalatinoLinotype TrueType WinAnsi yes yes no 82 0 DPOLGP+PalatinoLinotype,Italic TrueType WinAnsi yes yes no 85 0 FXXUVH+CMSY10 Type 1 Builtin yes yes no 92 0 DPOLGL+PalatinoLinotype,Bold TrueType WinAnsi yes yes no 103 0 DPOLGM+PalatinoLinotype CID TrueType Identity-H yes yes yes 106 0 DPOLGN+PalatinoLinotype TrueType WinAnsi yes yes no 112 0 DPOLGP+PalatinoLinotype,Italic TrueType WinAnsi yes yes no 115 0 DPOLGL+PalatinoLinotype,Bold TrueType WinAnsi yes yes no 129 0 DPOLGN+PalatinoLinotype TrueType WinAnsi yes yes no 132 0 DPOLGP+PalatinoLinotype,Italic TrueType WinAnsi yes yes no 135 0 MJVJIG+EURM10 Type 1 Builtin yes yes no 142 0 Jhove (Rel. 1.22.1, 2019-04-17) Date: 2023-06-08 02:27:24 CEST RepresentationInformation: pmc_9913695.pdf ReportingModule: PDF-hul, Rel. 1.12.1 (2019-04-17) LastModified: 2023-03-30 02:15:49 CEST Size: 1146358 Format: PDF Version: 1.7 Status: Well-Formed and valid SignatureMatches: PDF-hul MIMEtype: application/pdf PDFMetadata: Objects: 529 FreeObjects: 1 IncrementalUpdates: 0 DocumentCatalog: PageLayout: SinglePage PageMode: UseNone Outlines: Item: Title: Introduction Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@44c8afef Item: Title: Overview of the Hedgehog Signalling Pathway in Mammals Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@7b69c6ba Item: Title: General Models of Oncogenic Hh Pathway Activation Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@46daef40 Children: Item: Title: Ligand-Independent Hh Activation (Mutational) Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@12f41634 Item: Title: Ligand-Dependent Hh Activation (Non-Mutational) Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@13c27452 Item: Title: Non-Canonical Hh Activation (Non-Mutational) Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@262b2c86 Item: Title: Oncogenic Role of the Hedgehog Pathway in RMS Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@371a67ec Item: Title: Hedgehog Inhibitors and Clinical Trials Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@5ed828d Children: Item: Title: SMO Inhibitors Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@50d0686 Item: Title: GLI Inhibitors Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@7a3d45bd Item: Title: Hh Inhibitors in RMS: From Encouraging Preclinical Data to Disappointing Clinical Results Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@1e7c7811 Item: Title: Conclusions Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@77ec78b9 Item: Title: References Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@1a3869f4 Info: Title: Targeting the Hedgehog Pathway in Rhabdomyosarcoma Author: Patricia Zarzosa, Lia Garcia-Gilabert, Raquel Hladun, Gabriela Guillén, Gabriel Gallo-Oller, Guillem Pons, Julia Sansa-Girona, Miguel F. Segura, Josep Sánchez de Toledo, Lucas Moreno, Soledad Gallego and Josep Roma Subject: Aberrant activation of the Hedgehog (Hh) signalling pathway is known to play an oncogenic role in a wide range of cancers; in the particular case of rhabdomyosarcoma, this pathway has been demonstrated to be an important player for both oncogenesis and cancer progression. In this review, after a brief description of the pathway and the characteristics of its molecular components, we describe, in detail, the main activation mechanisms that have been found in cancer, including ligand-dependent, ligand-independent and non-canonical activation. In this context, the most studied inhibitors, i.e., SMO inhibitors, have shown encouraging results for the treatment of basal cell carcinoma and medulloblastoma, both tumour types often associated with mutations that lead to the activation of the pathway. Conversely, SMO inhibitors have not fulfilled expectations in tumours among them sarcomas mostly associated with ligand-dependent Hh pathway activation. Despite the controversy existing regarding the results obtained with SMO inhibitors in these types of tumours, several compounds have been (or are currently being) evaluated in sarcoma patients. Finally, we discuss some of the reasons that could explain why, in some cases, encouraging preclinical data turned into disappointing results in the clinical setting. 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