Liersch / Berdel / Kessler Angiogenesis Inhibition

1. Auflage 2009
ISBN: 978-3-540-78281-0
Verlag: Springer Berlin Heidelberg
Format: PDF
Kopierschutz: 1 - PDF Watermark

E-Book, Englisch, Band 180, 231 Seiten

Reihe: Recent Results in Cancer Research

Angiogenesis is attracting increased scientific and clinical interest. The identification of novel mediators and targeting molecules has led to significant progress in our understanding of tumor angiogenesis and tumor vessel targeting. Important advances in cancer treatment have already emerged, and in the future, blood vessel targeting will play a significant role within individualized therapeutic strategies. This volume provides a general overview of the latest developments in angiogenesis inhibition in cancer. All aspects from the bench to the bedside are considered, with detailed attention both to basic research and to its translation into clinical practice. Individual chapters are devoted to the roles of angiopoietins, HIF-1a, chemokines, PDGF and VEGF, and vascular integrins. The latest results of clinical trials are presented, and various advanced targeting strategies are discussed. This book will be invaluable to all who wish to learn of the most recent advances in this exciting field.

Autoren/Hrsg.

Liersch, Rüdiger

Berdel, Wolfgang E.

Kessler, Torsten

Inhaltsverzeichnis

1;Recent Results in Cancer Research;1
1.1;Introduction;14
1.1.1;Judah Folkman;14
1.2;Angiopoietins;15
1.2.1;Introduction;15
1.2.2;Importance of the Angiopoietin/Tie System During Developmental Angiogenesis;16
1.2.3;Angiopoietins and Tumor-Associated Angiogenesis;18
1.2.4;Therapeutic Implications;21
1.2.5;Conclusions;21
1.2.6;References;22
1.3;HIF-1a and Cancer Therapy;26
1.3.1;Background;26
1.3.2;Molecular and Cellular Biology of HIF-1;27
1.3.3;HIF-1 Regulation;27
1.3.3.1;Regulation of HIF-1a Translation;27
1.3.3.2;Regulation of HIF-1a Degradation;31
1.3.3.3;Regulation of HIF-1 Transactivation;32
1.3.4;Relationship Between HIF-1 and Other Key Oncogenic Pathways;33
1.3.4.1;HIF-1 Activation by Growth Factors;33
1.3.4.2;Interplay Between HIF-1 and the p53 Tumor Suppressor;33
1.3.4.3;Interplay Between HIF-1 and Myc;33
1.3.5;Hypoxia and HIF-1 Effects on Cancer Stem Cells;34
1.3.6;HIF-1 as a Cancer Drug Target;34
1.3.7;HIF-1 Inhibitors;35
1.3.8;Conclusions;38
1.3.9;References;39
1.4;Chemokines;46
1.4.1;4.1Angiogenesis;46
1.4.2;4.2Chemokines in Angiogenesis;48
1.4.2.1;4.2.1CXC Chemokine Subfamily;48
1.4.2.2;4.2.2CC Chemokine Subfamily;49
1.4.2.3;4.2.3CX3C Chemokine Subfamily;50
1.4.3;4.3Chemokine Receptor Repertoire of Endothelial Cells;50
1.4.4;4.4Angiogenesis, Chemokines, and Cancer;51
1.4.4.1;4.4.1Breast Cancer;52
1.4.4.2;4.4.2Malignant Melanoma;52
1.4.4.3;4.4.3Lung Cancer;53
1.4.5;4.5Inhibition of Chemokine-Induced Angiogenesis as a Therapeutic Strategy;54
1.4.6;References;56
1.5;Angiogenesis Inhibition in Cancer Therapy;62
1.5.1;5.1Introduction;62
1.5.2;5.2VEGF;63
1.5.2.1;5.2.1VEGF Isoforms and Their Expression;63
1.5.2.2;5.2.2VEGF Receptors;64
1.5.2.3;5.2.3Structure of VEGFR1 and VEGFR2;65
1.5.2.4;5.2.4Signaling and Biological Functions of VEGFR1;66
1.5.2.5;5.2.5Expression and Signaling of VEGFR2;67
1.5.2.6;5.2.6VEGF and Malignancy;68
1.5.3;5.3PDGF;70
1.5.3.1;5.3.1Platelet-Derived Growth Factor and Its Isoforms;70
1.5.3.2;5.3.2PDGF Receptors;72
1.5.3.3;PDGF Ligand and Receptor Expression Patterns;72
1.5.3.4;5.3.4PDGF Biosynthesis, Secretion, and Distribution;73
1.5.3.5;5.3.5PDGFR Signal Transduction;75
1.5.3.6;5.3.6Cellular Responses to PDGFR Signaling;76
1.5.3.7;5.3.7PDGF and PDGFR in Malignancy;78
1.5.4;References;80
1.6;Vascular Integrins: Therapeutic and Imaging Targets of Tumor Angiogenesis;93
1.6.1;Integrin Structure;93
1.6.2;Integrin Functions;94
1.6.2.1;Cell Adhesion;94
1.6.2.2;Cell Signaling;94
1.6.3;Integrins in Tumor Angiogenesis;96
1.6.4;Integrin Antagonists with Antiangiogenic Activities;97
1.6.4.1;Antibodies;97
1.6.4.2;Endogenous Antagonists;99
1.6.4.3;Peptides;100
1.6.4.4;Non-peptidic Inhibitors;100
1.6.5;Open Questions and Current Developments;101
1.6.5.1;Most Relevant Targets;101
1.6.5.2;Combination Therapies;101
1.6.5.3;Drug Targeting;102
1.6.5.4;Tumor Imaging;103
1.6.6;Future Directions;103
1.6.6.1;New Generation of Extracellular Antagonists;103
1.6.6.2;Targeting the Integrin Intracellular Domains;104
1.6.6.3;Targeting Angiogenic Precursor Cells and Inflammatory Cells;104
1.6.7;Conclusions;104
1.6.8;References;105
1.7;PDGF and Vessel Maturation;112
1.7.1;Introduction;112
1.7.2;The PDGF Family;112
1.7.3;Pericytes;113
1.7.3.1;Role of Pericytes;113
1.7.3.2;Identification of Pericytes;113
1.7.3.3;The Origin of Pericytes;114
1.7.4;Vessel Maturation;115
1.7.4.1;Normal Vessels;115
1.7.4.2;Tumor Vessels;117
1.7.5;Tumor Therapy Targeting PDGF Receptors on the Vasculature;118
1.7.5.1;Antiangiogenic Therapy Targeting Pericytes;119
1.7.5.2;Improving the Efficacy of Conventional Therapies;119
1.7.6;Future Perspectives;120
1.7.7;References;121
1.8;Lymphangiogenesis in Cancer: Current Perspectives;124
1.8.1;Introduction;124
1.8.2;Embryonic Lymphatic Development;125
1.8.3;The Lymphatic Function;126
1.8.3.1;Molecular Players in the Regulation of Lymphangiogenesis;127
1.8.4;Pathology of the Lymphatic Vasculature;131
1.8.4.1;Secondary Lymphedema;131
1.8.4.2;Primary Lymphedema;132
1.8.5;Role of Lymphangiogenesis in Cancer;133
1.8.5.1;Lymphvascular Invasion;133
1.8.5.2;Tumor-Lymphangiogenesis;133
1.8.5.3;Lymphatic Endothelial Cell Activation;134
1.8.5.4;Lymph Node Lymphangiogenesis;134
1.8.6;Targeting Lymphangiogenesis;135
1.8.6.1;Antibodies;136
1.8.6.2;Soluble Receptors;136
1.8.6.3;Small Molecule Inhibitor;136
1.8.7;Conclusions;136
1.8.8;References;136
1.9;Compounds in Clinical Phase III and Beyond;145
1.9.1;Introduction;145
1.9.1.1;Anti-VEGF Antibody (Bevacizumab, Avastin™);146
1.9.1.2;Aflibercept (VEGF – Trap);148
1.9.1.2.1;Sorafenib (Nexavar™);148
1.9.1.3;Sunitinib Malate (SU11248; Sutent™);152
1.9.1.4;Axitinib (AG-013736);154
1.9.1.5;Cediranib (AZD2171; Recentin™);155
1.9.1.6;Vandetanib (ZD6474; Zactima®);156
1.9.1.7;Vatalanib (PTK787/ZK222584);157
1.9.1.8;Endostatin (rh-Endostatin, YH-16, Endostar™);158
1.9.1.9;Thalidomide;159
1.9.1.10;Vascular Disrupting Agents;160
1.9.2;Accidental Antiangiogenesis Agents;162
1.9.2.1;Conclusions and Future Perspectives;163
1.9.3;References;164
1.10;Metronomic Chemotherapy: Principles and Lessons Learned from Applications in the Treatment of Metastatic Prostate Cancer;172
1.10.1;Introduction;172
1.10.2;Mechanisms of Action of Metronomic Chemotherapy;173
1.10.2.1; Preferential Antiproliferative Effects of Metronomic Chemotherapy Toward Endothelial Cells;174
1.10.2.2;Circulating Bone Marrow-Derived Endothelial Precursor Cells as Targets of Metronomic Chemotherapy;174
1.10.2.2.1;Benefit of Combined Bolus and Metronomic Chemotherapy Administration;175
1.10.2.2.2;CEPs and Optimal Biological Dose of Antiangiogenic Agents;176
1.10.2.3;Mechanisms of Action Summarized;177
1.10.3;Metronomic Chemotherapy for the Treatment of Metastatic Castration-Resistant Prostate Cancer;177
1.10.3.1;From Bench to Bedside;179
1.10.3.2;Key Findings of Metronomic Trials in Castration-Resistant Prostate Cancer and Emerging Questions;181
1.10.3.2.1;Choice of Cytotoxic Drugs Used in Metronomic Regimens;183
1.10.3.2.2;Optimal Biological Dose;183
1.10.3.2.3;Combination Therapies;184
1.10.3.3;Integration of Metronomic Chemotherapy into Current Standards of Practice for Prostate Cancer;185
1.10.4;Conclusions and Perspectives;185
1.10.5;References;186
1.11;Targeting Inflammatory Cells to Improve Anti-VEGF Therapies in Oncology;191
1.11.1;Role of Bone Marrow-Derived Tumor Infiltrating Cells in Tumor Angiogenesis;191
1.11.2;Endothelial Progenitor Cells (EPCs) and Circulatory Endothelial Progenitor Cells (CEPs);192
1.11.3;Tumor-Associated Macrophages;195
1.11.4;CD11b+ Gr1+ Myeloid-Derived Suppressor Cells;197
1.11.5;Lymphocytes and Mast Cells (MCs);197
1.11.6;Neutrophils;198
1.11.7;Therapeutic Targets to Overcome Anti-VEGF Refractoriness;199
1.11.7.1;Bv8;199
1.11.8;VEGF-B, -C, -D, and PlGF;199
1.11.9;Targeting MDSCs and TAMs;200
1.11.10;Targeting EPCs;201
1.11.11;Conclusions;201
1.11.12;References;201
1.12;Antibody-Based Vascular Tumor Targeting;207
1.12.1;Concept and Definitions;207
1.12.2;Discovery of Novel Vascular Targets;209
1.12.3;Validated Markers of the Tumor Vasculature;210
1.12.3.1;Extra Domains of Fibronectin;211
1.12.3.2;Large Isoforms of Tenascin C;212
1.12.3.3;Phosphatidylserine;212
1.12.3.4;Annexin A1;212
1.12.3.5;Prostate-Specific Membrane Antigen (PSMA);213
1.12.3.6;Endoglin;213
1.12.3.7;Integrins;213
1.12.3.8;Vascular Endothelial Growth Factors (VEGFs) and Receptors;214
1.12.3.9;Nucleolin;214
1.12.4;Vascular Tumor Targeting: Imaging Applications;214
1.12.5;Vascular Tumor Targeting: Therapeutic Applications;215
1.12.6;References;218
1.13;Caveolae and Cancer;223
1.13.1;Vascular Endothelium;223
1.13.2;Caveolae Structure;224
1.13.3;Isolation of Caveolae;224
1.13.4;Caveolae in Signal Transduction;225
1.13.5;Caveolae as Active Transport Vesicles;226
1.13.6;Vascular Targeting;227
1.13.7;Phage Display Libraries;228
1.13.8;Large-Scale Approaches;229
1.13.9;Reducing Complexity;229
1.13.10;Tissue-Specific Targets;230
1.13.11;Tumor-Specific Targets;231
1.13.12;Clinical Implications;232
1.13.13;References;233