Targeting the Sonic Hedgehog Signaling Pathway: Review of Smoothened and GLI Inhibitors
Abstract
:1. Introduction
1.1. Shh Signaling Pathway Overview
1.2. Shh Signaling in Cancer
1.2.1. Shh Signaling in Cancer Stem Cells
1.2.2. Novel GLI1 Isoform (tGLI1) in Cancer
2. SMO and GLI Inhibitors
2.1. SMO Inhibitors
Compound | Organization | Target | Cancer Type | Clinical Trial | NCT Trial |
---|---|---|---|---|---|
GDC-0449 (Vismodegib/Erivedge) | Roche/Genentech/Curis | SMO | Basal Cell Carcinoma - - - - - - - Advanced/Metastatic Basal Cell Carcinoma Basal Cell Nevus Syndrome Medulloblastoma - Recurrent Medulloblastoma Metastatic Castration-Resistant Prostate Cancer Chondrosarcoma Advanced Pancreatic Cancer Metastatic Pancreatic Cancer Myelofibrosis Metastatic Gastric & Esophageal Cancer Advanced Prostate Adenocarcinoma Small-Cell Lung Cancer Keratocystic Odontogenic Tumor Advanced Solid Tumors Acute Myeloid Leukemia Intracranial Meningioma | Phase II | NCT01835626 |
Phase I | NCT02639117 | ||||
Phase II | NCT02067104 | ||||
Phase 0 | NCT01631331 | ||||
Phase II | NCT01815840 | ||||
Phase II | NCT01700049 | ||||
Phase II | NCT01898598 | ||||
Phase IV | NCT02436408 | ||||
Phase II | NCT01367665 | ||||
- | - | ||||
Phase II | NCT01556009 | ||||
Phase II | NCT00957229 | ||||
Phase I/II | NCT01601184 | ||||
Phase II | NCT01878617 | ||||
Phase II | NCT01239316 | ||||
Phase II | NCT00939484 | ||||
Phase 0 | NCT02115828 | ||||
- | - | ||||
- | - | ||||
Phase II | NCT01267955 | ||||
Phase II | NCT01195415 | ||||
- | - | ||||
Phase I | NCT00878163 | ||||
Phase II | NCT01088815 | ||||
Phase I | NCT02593760 | ||||
Phase II | NCT00982592 | ||||
- | - | ||||
Phase I/II | NCT01163084 | ||||
- | - | ||||
Phase II | NCT00887159 | ||||
Phase II | NCT02366312 | ||||
- | - | ||||
Phase II | NCT02091141 | ||||
Phase II | NCT02073838 | ||||
Phase II | NCT02523014 | ||||
LDE225 (Erismodegib/Sonidegib/Odomzo®) | Novartis | SMO | Prostate Cancer Castration-Resistant Prostate Cancer Pancreatic Adenocarcinoma Advanced/Metastatic Pancreatic Cancer Refractory Multiple Myeloma Recurrent Ovarian Cancer Triple-Negative Breast Cancer Myeloid Malignancies Basal Cell Carcinoma Advanced/Metastatic Basal Cell Carcinoma - Advanced Solid Tumors - | Phase I | NCT02111187 |
Phase I | NCT02182622 | ||||
- | - | ||||
Phase I/II | NCT01431794 | ||||
- | - | ||||
Phase I/II | NCT02358161 | ||||
- | - | ||||
Phase II | NCT02086552 | ||||
- | - | ||||
Phase I/II | NCT02195973 | ||||
Phase I | NCT02027376 | ||||
- | - | ||||
Phase I | NCT02129101 | ||||
Phase II | NCT00961896 | ||||
Phase II | NCT00961896 | ||||
Phase 0 | NCT02303041 | ||||
Phase II | NCT01327053 | ||||
Phase I | NCT01769768 | ||||
Phase I | NCT01954355 | ||||
LDE225 (Erismodegib/Sonidegib/Odomzo®) | Novartis | SMO | Advanced Gastroesophageal Adenocarcinoma Small Cell Lung Cancer Myelofibrosis Advanced/Metastatic Hepatocellular Carcinoma Relapsed Medulloblastoma | Phase I | NCT02138929 |
- | - | ||||
- | - | ||||
Phase I | NCT01579929 | ||||
Phase I/II | NCT01787552 | ||||
Phase I | NCT02151864 | ||||
- | - | ||||
- | - | ||||
Phase II | NCT01708174 | ||||
- | - | ||||
BMS-833923/XL139 | Bristol Myers Squibb/Exelixis | SMO | Basal Cell Nevus Syndrome Chronic Myeloid Leukemia | Phase I | NCT02100371 |
- | - | ||||
Phase II | NCT01357655 | ||||
- | - | ||||
PF-04449913 (Glasdegib) | Pfizer | SMO | Myelofibrosis Chronic Myelomonocytic Leukemia Myelodysplastic Syndrome | Phase II | NCT02226172 |
Phase II | NCT01842646 | ||||
- | - | ||||
- | - | ||||
Phase II | NCT01842646 | ||||
- | - | ||||
LY2940680 (Taladegib) | Ignyta | SMO | Esophageal Cancer Advanced Solid Tumors | Phase I/II | NCT02530437 |
Phase I | NCT01919398 | ||||
- | - | ||||
IPI-926 (Saridegib) | Infinity | SMO | Advanced Pancreatic Adenocarcinoma | Phase I | NCT01383538 |
- | - | ||||
Arsenic Trioxide (ATO) | - | GLI1 | Non-Small-Cell Lung Cancer Small Cell Lung Cancer Acute Myeloid Leukemia Hepatocellular Carcinoma - Malignant Glioma Myelofibrosis Acute Promyelocytic Leukemia - - - - - - - - Chronic Myelogenous Leukemia Acute Myeloid Leukemia Myelodysplastic Syndrome Chronic Myelomonocytic Leukemia | Phase I | NCT02066870 |
- | - | ||||
Phase II | NCT01470248 | ||||
Phase II | NCT01835288 | ||||
- | - | ||||
- | - | ||||
- | - | ||||
Phase II | NCT02018757 | ||||
Phase I/II | NCT00275067 | ||||
Phase I | NCT01014546 | ||||
Phase III | NCT02339740 | ||||
Phase II | NCT01404949 | ||||
Phase II | NCT01409161 | ||||
Phase III | NCT00378365 | ||||
Phase IV | NCT01987297 | ||||
Phase III | NCT00866918 | ||||
Phase II | NCT00413166 | ||||
Phase II | NCT00551460 | ||||
Phase III | NCT00482833 | ||||
Phase IV | NCT02200978 | ||||
Phase I | NCT01397734 | ||||
- | - | ||||
Phase II | NCT02188706 | ||||
Phase II | NCT02190695 | ||||
Phase II | NCT02188706 | ||||
Phase II | NCT02190695 | ||||
Phase II | NCT02190695 | ||||
- | - | ||||
- | - |
2.1.1. Cyclopamine
2.1.2. GDC-0449 (Vismodegib/Erivedge)
2.1.3. LDE-225 (Erismodegib/Sonidegib/Odomzo)
2.1.4. IPI-926 (Saridegib)
2.1.5. CUR61414
2.1.6. BMS-833923/XL139
2.1.7. PF-04449913 (Glasdegib)
2.1.8. PF-5274857
2.1.9. TAK-441
2.1.10. LY2940680 (Taladegib)
2.1.11. MRT-92
2.1.12. Jervine
2.2. GLI Inhibitors
2.2.1. GANTs
2.2.2. Arsenic Trioxide (ATO)
2.3. Shh Inhibitors
2.3.1. RU-SKI 43
2.3.2. Shh Monoclonal Antibody 5E1
2.4. Therapeutic Targets Regulated by tGLI1
Name | Company | Molecular Target(s) | Clinical Indications |
---|---|---|---|
Sorafenib (Nexavar) | Bayer Onyx Pharmaceuticals | VEGFR1-3 [159] PDGFRβ Raf | Unresectable Hepatocellular Carcinoma [160] Renal Cell Carcinoma [161] Radiation-Resistant Thyroid Cancer [162] |
Sunitinib (Sutent) | Pfizer | VEGFR2 [163] PDGFRβ [164] Flt3 [164] | Renal Cell Carcinoma [165] Imatinib-Resistant Gastrointestinal Stroma Tumors [166] |
Pazopanib (Votrient) | GlaxoSmithKline | VEGFR1-3 [167] PDGFR FGFR1-3 EGFR c-Kit | Metastatic Renal Cell Carcinoma [168] Metastatic Soft Tissue Sarcoma [169] |
Regorafenib (Stivarga) | Bayer | VEGFR1-3 [170] PDGFRβ FGFR-1 KIT RET B-Raf | Metastatic Colorectal Cancer [171] Metastatic Gastrointestinal Stromal Tumors [172] |
Vandetanib (Caprelsa) | Genzyme | VEGFR2-3 [173] EGFR RET | Metastatic Medullary Thyroid Cancer [174] |
Cabozantinib (Cometriq) | Exelixis | VEGFR2 [175] c-MET RET | Medullary Thyroid Cancer [176] |
Lenvatinib (Lenvima) | Eisai Inc | VEGFR1-3 [177] FGFR1-4 PDGFRα c-Kit RET | Radiation-Resistant Differentiated Thyroid Cancer [178] |
Axitinib(Inlyta) | Pfizer | VEGFR1-3 [179] PDGFRα,β c-Kit | Renal Cell Carcinoma [180] |
Ramucirumab (Cyramza) | Eli Lilly | VEGFR2 [181] | Gastric Adenocarcinoma [182] Gastro-Esophageal Junction Adenocarcinoma [182] Metastatic Non-Small-Cell Lung Cancer [183] |
3. Conclusions
Acknowledgments
Author Contributions
Conflicts of Interest
References
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Rimkus, T.K.; Carpenter, R.L.; Qasem, S.; Chan, M.; Lo, H.-W. Targeting the Sonic Hedgehog Signaling Pathway: Review of Smoothened and GLI Inhibitors. Cancers 2016, 8, 22. https://doi.org/10.3390/cancers8020022
Rimkus TK, Carpenter RL, Qasem S, Chan M, Lo H-W. Targeting the Sonic Hedgehog Signaling Pathway: Review of Smoothened and GLI Inhibitors. Cancers. 2016; 8(2):22. https://doi.org/10.3390/cancers8020022
Chicago/Turabian StyleRimkus, Tadas K., Richard L. Carpenter, Shadi Qasem, Michael Chan, and Hui-Wen Lo. 2016. "Targeting the Sonic Hedgehog Signaling Pathway: Review of Smoothened and GLI Inhibitors" Cancers 8, no. 2: 22. https://doi.org/10.3390/cancers8020022