Hedgehog signaling activation in human cancer and its clinical implications (eBook)

Contents 6
Contributors 8
Chapter 1: Overview of Hedgehog Signaling Pathway 12
Introduction 12
Hh Signal Transduction 14
Lipid Modification and Multimerization of Hh 14
Heparan Sulfate Proteoglycans Regulate Hh Signaling 14
Modulation of Pathway Activity by Multiple Hh-Binding Proteins 15
Ptc Inhibits Smo Catalytically 15
Regulation of Smo Trafficking and Conformation 16
Downstream of Smo: G Protein and Cos2/Kif.7-Ci/Gli Signaling Complex 17
Control of Gli Protein Degradation and Processing 18
Sufu: A Key Regulator of Mammalian Hh Signaling 19
Unresolved Questions in Mammalian Hh Signaling 20
References 20
Chapter 2: Regulation of the Hedgehog Morphogene Gradient* 27
Introduction 27
Atypical Biosynthesis of Active Hh Signaling Peptide 28
Routing of Hh to the Plasma Membrane 28
Secretion and Release of Lipid-Modified Hh 30
Hedgehog Spreading: A Dilemma in Motion 32
Extracellular Gradient Formation by HSPGs 33
A Similar Spreading Mechanism from Flies to Mice? 35
Hh Uses Multiple Carriers for Its Travels 36
Conclusions 39
References 39
Chapter 3: Smoothened Signaling Through a G-Protein Effector Network 43
Introduction 43
Hedgehog Signal Transduction 44
Smoothened as a G-Protein-Coupled Receptor 45
SMO Signaling Through Heterotrimeric G-Proteins 47
A SMO-Dependent G-Protein Signaling Network 48
Small-Molecule Modulators of SMO 51
Future Directions 52
References 53
Chapter 4: Kinases and Phosphatases in Hedgehog Signaling 58
Phosphorylation Events in Hh Signaling 59
Kinases Regulating the Transcriptional Factor, Ci./Gli 60
Kinases Mediating the Activation of Smo in Response to Hh 62
Non-conserved Mechanisms of Regulation by Kinases 64
Phosphatases in Hh Signaling 65
Gradient Hh Signaling Activity Is Interpreted by Differential Phosphorylation of the Intracellular Components 66
References 68
Chapter 5: Signaling Cross-Talk of Oncogenic KRAS and Hedgehog Pathways in Pancreatic Cancer 74
Introduction 74
KRAS Signaling and PDA 75
Cross-Talk Between KRAS and Hh Signaling in Cancer 77
Anticancer Therapeutics Targeting KRAS or Hh Pathway 79
Conclusion 82
References 82
Chapter 6: Hedgehog and Protein Kinase C Signaling 86
Introduction 86
Protein Kinase C 86
Functions of Different PKC Isoforms in Human Cancer 87
Crosstalk of HH and PKC 88
Crosstalk of HH and PKC in Development 89
Crosstalk of HH and PKC in Stem Cells 90
Crosstalk of HH and PKC in Human Cancer 90
MEK/ERK Pathway in PKC-Mediated HH Signaling 91
Summary 91
References 91
Chapter 7: Activation of Hedgehog Signaling in Human Cancer 93
Introduction 93
Signal Transduction of the Hedgehog Pathway 94
The Link of Hh Signaling to Human Cancer 97
Activation of the Hedgehog Pathway in Human Cancer 97
BCCs and Medulloblastomas 97
Activation of Hh Signaling in Cancers Not Associated with Gorlin Syndrome 99
The Role of Hh Signaling in Cancer Initiation, Progression, and Metastasis 99
Animal Models for Hh-Mediated Carcinogenesis 100
Mouse Models for BCCs 101
Mouse Models for Medulloblastomas 101
Mouse Models for Hh Signaling-Mediated Carcinogenesis in Other Organ Sites 102
Small Molecule Modulators of Hedgehog Signaling 103
Natural Products (Cyclopamine, Its Derivatives, and Others) 103
Synthetic Hh Signaling Antagonists 104
Hh Signaling Modulators 104
Summary 105
References 105
Chapter 8: Hedgehog Signaling in Pediatric Brain Tumors 113
Introduction 113
Role of SHH Signaling in CNS Development 113
Dorso-Ventral Polarity and SHH Signaling 114
Rapid Expansion of Cells in the Region of the Developing Brain 115
Brain Boundaries 116
Regional Specification of the Developing Brain 116
Forebrain 116
Midbrain and Hindbrain 117
Cerebellum 118
Aberrant Activation of SHH Signaling in Pediatric Brain Tumors 120
Genetic Alteration of Components of the SHH Pathway in Pediatric Brain Tumors 120
Medulloblastoma: Clinical Aspects 121
Medulloblastoma: Biologic Aspects 123
Medulloblastoma: Dysregulation of SHH Signaling 125
Other Pathways Affecting SHH Signaling in Medulloblastoma 126
Dysregulation of SHH Components in Other Pediatric Brain Tumors 128
Potential Clinical Applications of HH Pathway Inhibitors in the Treatment of Patients with Pediatric Brain Tumors 129
Summary 131
References 132
Chapter 9: Hedgehog Signaling in Mammary Gland Development and Breast Cancer 139
Introduction 139
Mammalian Hedgehog Signaling 139
Non-canonical Hedgehog Network Functions 140
Hedgehog Network Control of Mammary Gland Development and Breast Cancer 142
Mammary Gland Development 142
Hedgehog Network Gene Expression and Function in Mammary Gland Development 143
Role of Primary Cilia in Mammary Gland Hedgehog Signaling 147
The Hedgehog Network in Breast Cancer 147
Hedgehog Signaling as a Therapeutic Target in Breast Cancer 150
References 153
Chapter 10: Hedgehog Signaling and Cancer Treatment Resistance 158
Introduction 158
Cancer Treatment Resistance 159
The Role of Hedgehog Signaling in CancerTreatment Resistance 160
Induction of Tumor Regrowth and Cancer Stem Cells 161
Anti-apoptosis and Cell Cycle Regulation 161
Repair of DNA Damage 162
Stimulation of Multiple Drug Resistant Transporter System 163
Development of HH Regulating Therapeutics 164
Concluding Remark 165
References 165
Chapter 11: Small-Molecule Inhibitors of the Hedgehog Pathway 169
Introduction 169
Hedgehog Signaling Mechanisms and Cancer 170
Small-Molecule Inhibitors of Smoothened 173
Small-Molecule Inhibitors that Act Upstream of Smoothened 180
Small-Molecule Inhibitors that Act Downstream of Smoothened 184
Conclusions and Future Directions 186
References 187
Chapter 12: Cyclopamine and Its Derivatives for Cancer Therapeutics 193
Introduction 193
Cyclopamine, a Natural Steroidal Alkaloid from Veratrum Species: Extraction, Isolation, and Structure Elucidation 195
Synthetic Chemistry of Cyclopamine 196
Evaluation of Cyclopamine as Drug Lead: Its Drug Properties 198
Medicinal Chemistry of Cyclopamine Analogs 200
Discovery and Development of IPI-926, a Semisynthetic Cyclopamine Derivative in Clinical Trials 203
Preclinical Pharmacology of IPI-926 206
Clinical Application 212
Conclusion 212
References 213
Index 219