Targeting the Hedgehog Pathway in Rhabdomyosarcoma
Abstract
Simple Summary
Abstract
1. Introduction
2. Overview of the Hedgehog Signalling Pathway in Mammals
3. General Models of Oncogenic Hh Pathway Activation
3.1. Ligand-Independent Hh Activation (Mutational)
3.2. Ligand-Dependent Hh Activation (Non-Mutational)
3.3. Non-Canonical Hh Activation (Non-Mutational)
4. Oncogenic Role of the Hedgehog Pathway in RMS
5. Hedgehog Inhibitors and Clinical Trials
5.1. SMO Inhibitors
Study | Clinical Trials. gov Identifier | Inhibitor Name | Activity | Tumour Type | Phase | Outcome |
---|---|---|---|---|---|---|
Vismodegib in Treating Patients with Advanced Chondrosarcomas | NCT01267955 | Vismodegib (GDC-0449) | SMO inhibitor | Chondrosarcoma | Phase II | Clinical benefit was achieved after 6 months in 25.6% of patients [91] |
Vismodegib and Gamma-Secretase/Notch Signalling Pathway Inhibitor RO4929097 in Treating Patients with Advanced or Metastatic Sarcoma | NCT01154452 | Vismodegib (GDC-0449) | SMO inhibitor | Adult rhabdomyosarcoma and other advanced/metastatic sarcomas | Phase I Phase II | The combination therapy was safe but Vismodegib did not significantly improve the clinical efficacy of RO4929097 [93] |
A Phase I Dose Finding and Safety Study of Oral LDE225 in Children and a Phase II Portion to Assess Preliminary Efficacy in Recurrent or Refractory MB | NCT01125800 | Sonidegib (LDE225) | SMO inhibitor | Rhabdomyosarcoma and other paediatric tumours potentially dependent on the Hh pathway | Phase I Phase II | Only the SHh subgroup of medulloblastoma patients, as defined by a five-gene signature RT-PCR assay, responded [95] |
A Safety and Efficacy Study of Patients with Metastatic or Locally Advanced (Unresectable) Chondrosarcoma | NCT01310816 | Patidegib/Saridegib (IPI-926) | SMO inhibitor | Chondrosarcoma | Phase II | Ended prematurely. On 14 June 2012, a planned futility analysis of data from the study concluded that treatment with IPI-926 was similar to placebo and, therefore, the trial would not meet its primary endpoint |
A Study of LY2940680 in Paediatric Medulloblastoma or Rhabdomyosarcoma | NCT01697514 | Taladegib (LY2940680) | SMO inhibitor | Medulloblastoma and rhabdomyosarcoma | Phase I | Withdrawn (Trial stopped early for poor accrual) |
Arsenic Trioxide in Treating Patients with Advanced Neuroblastoma or Other Childhood Solid Tumours | NCT00024258 | Arsenic trioxide | GLI inhibitor | Sarcoma and other paediatric tumours | Phase II | The disease progressed in 72.7% and stabilized in 22.7% of the patients |
Arsenic Trioxide Plus Radiation Therapy in Treating Patients with Newly Diagnosed Malignant Glioma | NCT00045565 | Arsenic trioxide | GLI inhibitor | Gliosarcoma and other malignant glioma | Phase I | No results posted |
Study of Genistein in Paediatric Oncology Patients (UVA-Gen001) (UVA-Gen001) | NCT02624388 | Genistein | GLI inhibitor | Sarcoma and other paediatric tumours | Phase II | The therapy is safe and well tolerated |
5.2. GLI Inhibitors
6. Hh Inhibitors in RMS: From Encouraging Preclinical Data to Disappointing Clinical Results
7. Conclusions
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
References
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Zarzosa, P.; Garcia-Gilabert, L.; Hladun, R.; Guillén, G.; Gallo-Oller, G.; Pons, G.; Sansa-Girona, J.; Segura, M.F.; Sánchez de Toledo, J.; Moreno, L.; et al. Targeting the Hedgehog Pathway in Rhabdomyosarcoma. Cancers 2023, 15, 727. https://doi.org/10.3390/cancers15030727
Zarzosa P, Garcia-Gilabert L, Hladun R, Guillén G, Gallo-Oller G, Pons G, Sansa-Girona J, Segura MF, Sánchez de Toledo J, Moreno L, et al. Targeting the Hedgehog Pathway in Rhabdomyosarcoma. Cancers. 2023; 15(3):727. https://doi.org/10.3390/cancers15030727
Chicago/Turabian StyleZarzosa, Patricia, Lia Garcia-Gilabert, Raquel Hladun, Gabriela Guillén, Gabriel Gallo-Oller, Guillem Pons, Julia Sansa-Girona, Miguel F. Segura, Josep Sánchez de Toledo, Lucas Moreno, and et al. 2023. "Targeting the Hedgehog Pathway in Rhabdomyosarcoma" Cancers 15, no. 3: 727. https://doi.org/10.3390/cancers15030727
APA StyleZarzosa, P., Garcia-Gilabert, L., Hladun, R., Guillén, G., Gallo-Oller, G., Pons, G., Sansa-Girona, J., Segura, M. F., Sánchez de Toledo, J., Moreno, L., Gallego, S., & Roma, J. (2023). Targeting the Hedgehog Pathway in Rhabdomyosarcoma. Cancers, 15(3), 727. https://doi.org/10.3390/cancers15030727