Angiogenesis Inhibition (eBook)

Recent Results in Cancer Research 1
Introduction 14
Judah Folkman 14
Angiopoietins 15
Introduction 15
Importance of the Angiopoietin/Tie System During Developmental Angiogenesis 16
Angiopoietins and Tumor-Associated Angiogenesis 18
Therapeutic Implications 21
Conclusions 21
References 22
HIF-1a and Cancer Therapy 26
Background 26
Molecular and Cellular Biology of HIF-1 27
HIF-1 Regulation 27
Regulation of HIF-1a Translation 27
Regulation of HIF-1a Degradation 31
Regulation of HIF-1 Transactivation 32
Relationship Between HIF-1 and Other Key Oncogenic Pathways 33
HIF-1 Activation by Growth Factors 33
Interplay Between HIF-1 and the p53 Tumor Suppressor 33
Interplay Between HIF-1 and Myc 33
Hypoxia and HIF-1 Effects on Cancer Stem Cells 34
HIF-1 as a Cancer Drug Target 34
HIF-1 Inhibitors 35
Conclusions 38
References 39
Chemokines 46
4.1Angiogenesis 46
4.2Chemokines in Angiogenesis 48
4.2.1CXC Chemokine Subfamily 48
4.2.2CC Chemokine Subfamily 49
4.2.3CX3C Chemokine Subfamily 50
4.3Chemokine Receptor Repertoire of Endothelial Cells 50
4.4Angiogenesis, Chemokines, and Cancer 51
4.4.1Breast Cancer 52
4.4.2Malignant Melanoma 52
4.4.3Lung Cancer 53
4.5Inhibition of Chemokine-Induced Angiogenesis as a Therapeutic Strategy 54
References 56
Angiogenesis Inhibition in Cancer Therapy 62
5.1Introduction 62
5.2VEGF 63
5.2.1VEGF Isoforms and Their Expression 63
5.2.2VEGF Receptors 64
5.2.3Structure of VEGFR1 and VEGFR2 65
5.2.4Signaling and Biological Functions of VEGFR1 66
5.2.5Expression and Signaling of VEGFR2 67
5.2.6VEGF and Malignancy 68
5.3PDGF 70
5.3.1Platelet-Derived Growth Factor and Its Isoforms 70
5.3.2PDGF Receptors 72
PDGF Ligand and Receptor Expression Patterns 72
5.3.4PDGF Biosynthesis, Secretion, and Distribution 73
5.3.5PDGFR Signal Transduction 75
5.3.6Cellular Responses to PDGFR Signaling 76
5.3.7PDGF and PDGFR in Malignancy 78
References 80
Vascular Integrins: Therapeutic and Imaging Targets of Tumor Angiogenesis 93
Integrin Structure 93
Integrin Functions 94
Cell Adhesion 94
Cell Signaling 94
Integrins in Tumor Angiogenesis 96
Integrin Antagonists with Antiangiogenic Activities 97
Antibodies 97
Endogenous Antagonists 99
Peptides 100
Non-peptidic Inhibitors 100
Open Questions and Current Developments 101
Most Relevant Targets 101
Combination Therapies 101
Drug Targeting 102
Tumor Imaging 103
Future Directions 103
New Generation of Extracellular Antagonists 103
Targeting the Integrin Intracellular Domains 104
Targeting Angiogenic Precursor Cells and Inflammatory Cells 104
Conclusions 104
References 105
PDGF and Vessel Maturation 112
Introduction 112
The PDGF Family 112
Pericytes 113
Role of Pericytes 113
Identification of Pericytes 113
The Origin of Pericytes 114
Vessel Maturation 115
Normal Vessels 115
Tumor Vessels 117
Tumor Therapy Targeting PDGF Receptors on the Vasculature 118
Antiangiogenic Therapy Targeting Pericytes 119
Improving the Efficacy of Conventional Therapies 119
Future Perspectives 120
References 121
Lymphangiogenesis in Cancer: Current Perspectives 124
Introduction 124
Embryonic Lymphatic Development 125
The Lymphatic Function 126
Molecular Players in the Regulation of Lymphangiogenesis 127
Pathology of the Lymphatic Vasculature 131
Secondary Lymphedema 131
Primary Lymphedema 132
Role of Lymphangiogenesis in Cancer 133
Lymphvascular Invasion 133
Tumor-Lymphangiogenesis 133
Lymphatic Endothelial Cell Activation 134
Lymph Node Lymphangiogenesis 134
Targeting Lymphangiogenesis 135
Antibodies 136
Soluble Receptors 136
Small Molecule Inhibitor 136
Conclusions 136
References 136
Compounds in Clinical Phase III and Beyond 145
Introduction 145
Anti-VEGF Antibody (Bevacizumab, Avastin™) 146
Aflibercept (VEGF – Trap) 148
Sorafenib (Nexavar™) 148
Sunitinib Malate (SU11248 Sutent™)
Axitinib (AG-013736) 154
Cediranib (AZD2171 Recentin™)
Vandetanib (ZD6474 Zactima®)
Vatalanib (PTK787/ZK222584) 157
Endostatin (rh-Endostatin, YH-16, Endostar™) 158
Thalidomide 159
Vascular Disrupting Agents 160
Accidental Antiangiogenesis Agents 162
Conclusions and Future Perspectives 163
References 164
Metronomic Chemotherapy: Principles and Lessons Learned from Applications in the Treatment of Metastatic Prostate Cancer 172
Introduction 172
Mechanisms of Action of Metronomic Chemotherapy 173
Preferential Antiproliferative Effects of Metronomic Chemotherapy Toward Endothelial Cells 174
Circulating Bone Marrow-Derived Endothelial Precursor Cells as Targets of Metronomic Chemotherapy 174
Benefit of Combined Bolus and Metronomic Chemotherapy Administration 175
CEPs and Optimal Biological Dose of Antiangiogenic Agents 176
Mechanisms of Action Summarized 177
Metronomic Chemotherapy for the Treatment of Metastatic Castration-Resistant Prostate Cancer 177
From Bench to Bedside 179
Key Findings of Metronomic Trials in Castration-Resistant Prostate Cancer and Emerging Questions 181
Choice of Cytotoxic Drugs Used in Metronomic Regimens 183
Optimal Biological Dose 183
Combination Therapies 184
Integration of Metronomic Chemotherapy into Current Standards of Practice for Prostate Cancer 185
Conclusions and Perspectives 185
References 186
Targeting Inflammatory Cells to Improve Anti-VEGF Therapies in Oncology 191
Role of Bone Marrow-Derived Tumor Infiltrating Cells in Tumor Angiogenesis 191
Endothelial Progenitor Cells (EPCs) and Circulatory Endothelial Progenitor Cells (CEPs) 192
Tumor-Associated Macrophages 195
CD11b+ Gr1+ Myeloid-Derived Suppressor Cells 197
Lymphocytes and Mast Cells (MCs) 197
Neutrophils 198
Therapeutic Targets to Overcome Anti-VEGF Refractoriness 199
Bv8 199
VEGF-B, -C, -D, and PlGF 199
Targeting MDSCs and TAMs 200
Targeting EPCs 201
Conclusions 201
References 201
Antibody-Based Vascular Tumor Targeting 207
Concept and Definitions 207
Discovery of Novel Vascular Targets 209
Validated Markers of the Tumor Vasculature 210
Extra Domains of Fibronectin 211
Large Isoforms of Tenascin C 212
Phosphatidylserine 212
Annexin A1 212
Prostate-Specific Membrane Antigen (PSMA) 213
Endoglin 213
Integrins 213
Vascular Endothelial Growth Factors (VEGFs) and Receptors 214
Nucleolin 214
Vascular Tumor Targeting: Imaging Applications 214
Vascular Tumor Targeting: Therapeutic Applications 215
References 218
Caveolae and Cancer 223
Vascular Endothelium 223
Caveolae Structure 224
Isolation of Caveolae 224
Caveolae in Signal Transduction 225
Caveolae as Active Transport Vesicles 226
Vascular Targeting 227
Phage Display Libraries 228
Large-Scale Approaches 229
Reducing Complexity 229
Tissue-Specific Targets 230
Tumor-Specific Targets 231
Clinical Implications 232
References 233