Vascular Disruptive Agents for the Treatment of Cancer (eBook)

Dr. Tim Meyer is a Senior Lecturer in Medical Oncology at the UCL Cancer Institute in London where he specialises in gastrointestinal cancers and drug development. He trained in medicine at UCL and obtained his PhD from London University, after which he completed specialist training in medical oncology. His major research focus is antibody-based vascular targeting.

Vascular Disruptive Agentsfor the Treatment of Cancer 3
Contents 5
Contributors 7
Development of Vascular Disrupting Agents 10
1 Introduction 10
2 Early Studies Supporting the Development of Vascular Disrupting Cancer Therapies 14
2.1 Testicular Torsion 14
2.2 William Henry Woglom 15
2.3 Tumor Clamping Studies 15
2.4 Coley’s Toxins 16
3 Vascular Disrupting Therapies Employing High Molecular Weight Agents 17
3.1 Engineered Ligands 17
3.2 Antibody-Based Approaches 18
3.3 Gene Therapy 19
4 Small Molecule Vascular Disrupting Agents 21
4.1 Metals and Metalloids 21
4.2 Flavonoids/Xanthenones 21
4.3 N-Cadherin Antagonists 22
4.4 Colchicine 22
4.5 Novel Vascular Disrupting Tubulin Depolymerizing Agents 23
5 Combining VDAs with Other Therapies 25
6 Clinical Experience with VDAs 26
7 Concluding Remarks 28
References 28
Part I Pre-Clinical Development 37
The Discovery and Characterisation of Tumour Endothelial Markers 38
1 Vascular Tumor Targeting: Concepts and Definitions 38
2 Methodologies for the Discovery of Vascular Tumor Targets 39
3 Ligand-Based Pharmacodelivery Applications 42
4 Validated Vascular Tumor Targets 43
4.1 EDA and EDB Domains of Fibronectin 43
4.2 Extra Domains of Within Tenascin-C 44
4.3 Endoglin 44
4.4 Prostate-Specific Membrane Antigen 45
4.5 Annexin A1 45
4.6 Phosphatidylserine Phospholipids 45
4.7 VEGF-A and VEGF Receptors 46
4.8 Integrins 46
4.9 Robo4 46
4.10 Other TEM’s Endosialin/TEM1 and TEM7 47
5 Products in Clinical Development and Concluding Remarks 47
References 49
The Use of Animal Models in the Assessment of Tumour Vascular Disrupting Agents (VDAs) 56
1 Introduction 56
2 Animal Models 57
2.1 General Considerations 57
2.2 Subcutaneous and Other Ectopic Models 58
2.3 Orthotopic and Metastatic Models 59
2.4 Autochthonous Tumour Models 59
2.5 Isolated Limb Perfusion in Rats 60
2.6 Transgenic Knockout Mice 60
2.7 Zebrafish 61
3 Assays for Vascular Function 62
3.1 General Considerations 62
3.2 Blood Flow Rate 62
3.3 High Frequency Micro-ultrasound 63
3.4 Doppler Optical Coherence Tomography (DOCT) 65
3.5 Laser Doppler Flowmetry and Near Infrared Spectroscopy 65
3.6 Multifluorescence Microscopy 65
3.7 Matrigel Plug Assay 67
3.8 Intravital Video Microscopy 68
4 Assays for Vascular Morphology 69
4.1 Microvascular Corrosion Casting of Tumour Architecture 69
4.2 Transmission Electron Microscopy (TEM) 69
4.3 Confocal Laser Scanning Microscopy (CLSM) and Multi-Photon Fluorescence Microscopy (MPFM) 70
5 Non-invasive Imaging 71
5.1 General Considerations 71
5.2 Bioluminescence/Fluorescence Imaging 71
5.3 Nuclear Magnetic Resonance Spectroscopy (MRS) and Imaging (MRI) 72
5.4 Positron Emission Tomography (PET) 75
5.5 Scintigraphic Imaging of Tumour Hypoxia 75
6 Other Assays 76
6.1 Hollow Fibre Assay 76
6.2 Wick-in-Needle Method for the Measurement of Interstitial Fluid Pressure (IFP) 76
References 77
Combination Therapy with Chemotherapy and VDAs 83
1 Introduction 83
2 Combining VDAs and Chemotherapy 84
2.1 Complementary Targeting of Different Regions of the Tumor (Spatial Cooperation) 84
2.2 Synergistic Activity on the Same Tumor Compartment 90
2.3 Combination with Agents That Exploitthe Microenvironmental Changes Induced by VDAs 91
2.4 Combination with Agents That Potentiate the Activityof VDAs, Reduce Resistance to Them or Limit Their Toxicity 91
2.5 Modification in Blood Flow: Effects on Cytotoxic Drug Pharmacokinetics 92
3 Sequencing and Timing 93
4 Toxicity 95
5 Conclusions 96
References 97
Lessons from Animal Imaging in Preclinical Models 100
1 Magnetic Resonance Imaging of Tumour Vasculature 100
2 Why Use MRI for VDA Assessment? 101
3 Dynamic Contrast-Enhanced MRI 102
3.1 Preclinical Assessment of ZD6126 Using DCE-MRI 103
3.2 Preclinical Assessment of CA4P Using DCE-MRI 105
3.3 Preclinical Assessment of DMXAA Using DCE-MRI 106
3.4 Preclinical DCE-MRI Summary 107
4 Susceptibility Contrast MRI 108
4.1 Preclinical Assessment of VDAs Using Susceptibility Contrast MRI 108
5 Intrinsic Susceptibility MRI 109
5.1 Preclinical Assessment of VDAs Using Intrinsic Susceptibility MRI 109
6 Diffusion-Weighted MRI 111
6.1 Preclinical Assessment of VDAs Using DW-MRI 111
7 Magnetic Resonance Spectroscopy 112
7.1 Preclinical Assessment of VDAs Using Magnetic Resonance Spectroscopy 113
8 Non-MR Imaging Modalities 115
8.1 Fluorine-18 Fluorodeoxyglucose-Positron Emission Tomography ([18F]-FDG-PET) 115
8.2 Scintigraphic Imaging 116
8.3 High-Frequency Doppler Ultrasound 116
9 Chapter Summary 116
References 117
Combining Antiangiogenic Drugs with Vascular Disrupting Agents Rationale and Mechanisms of Action 122
1 Introduction and Background 123
2 Circulating Endothelial Progenitor Cells in Tumor Angiogenesis 125
2.1 Induction of Multiple Growth Factors, Cytokines, and Chemokines by Cytotoxic Agents, Including VDAs 130
2.2 Clinical Studies of Combination Vascular Disruptive Agent and Antiangiogenics 132
2.2.1 Study Design 133
2.2.2 Patient Population 134
2.2.3 Results 134
3 Conclusions and Summary 137
References 137
Part II maging in the Development of VascularDisruptive Agents 140
MRI to Assess Vascular Disruptive Agents 141
1 Introduction 141
2 Imaging the Vascularity of Tissues: Comparison of Methods 143
3 MRI for Assessing Tissue Vascularity 144
3.1 Biological Basis for Observations of Dynamic MRI 145
3.2 Quantification of DCE-MRI 146
3.3 Validation of DCE-MRI as a Vascular Biomarker 149
3.4 DCE-MRI in the Clinical Assessment of Antiangiogenic Agents 149
3.4.1 Phase I Studies 150
3.4.2 Antiangiogenic Agents as Monotherapy 151
3.4.3 Antiangiogenic Agents with Conventional Therapies 152
3.5 DCE-MRI in Pre-clinical Development of VDAs 152
4 DCE-MRI in the Clinical Development of VDAs 154
4.1 DMXAA 154
4.2 ZD6126 154
4.3 CA4P 158
4.4 CA1P (OXi-4503) 160
5 VDA Experience with Positron Emission Tomography (PET) 161
6 VDA Experience with Perfusion ComputedTomography (CT) 162
7 Conclusions 162
References 163
Contrast Ultrasound in Imaging Tumor Angiogenesis 168
1 Background 169
2 Imaging of Tumor Angiogenesis 170
3 Contrast Ultrasound 171
3.1 Targeted Imaging with Microbubbles-Enhanced Ultrasound 172
3.2 Imaging Tumor Angiogenesis with Targeted MB and Ultrasound 173
4 Conclusions 175
References 177
Part III Clinical Development 183
The Clinical Development of Tubulin Binding Vascular Disrupting Agents 184
1 Introduction 184
2 Combretastatin A4 185
2.1 Preclinical Development 185
2.1.1 Structure and Mechanism of Action 185
2.1.2 In Vivo Antitumor Efficacy 186
CA4P Single-Agent Activity 186
CA4P Combination Activity 187
2.1.3 Preclinical Administration Schedule: Infusion Frequency and Duration 188
2.1.4 Animal Toxicity 189
2.2 Clinical Development 190
2.2.1 Phase I Trials 190
2.2.2 Trials of CA4P in Combination with Cytotoxic Agents 196
2.2.3 CA4P in Combination with Radiotherapy or Antibodies 199
2.2.4 Toxicity 199
2.2.5 Pharmacokinetics 200
2.2.6 Pharmacodynamics: Imaging the Effects of Vasculature-Targeting Agents 202
2.3 Conclusion 203
3 Other Tubulin Binding VDAs 204
3.1 ZD6126 (ANG453) 204
3.2 AVE8062 205
3.3 OXi4503 206
3.4 Dolastatin-10 (NSC-376128) 207
3.5 Cemadotin (LU103793, NSC D-669356) 207
3.6 TZT-1027 207
3.7 ILX651 208
3.8 NPI-2358 209
3.9 MN-029 209
3.10 ABT-751 209
3.11 BNC-105P 210
3.12 EPC-2407 210
3.13 LP-261 211
3.14 CYT-997 211
3.15 Other Tubulin Binding VDAs in Development 211
References 212
ASA404 (DMXAA): New Concepts in Tumour Vascular Targeting Therapy 218
1 Introduction 218
2 Preclinical Development 219
2.1 Tumour Vasculature as a Target 220
2.2 Cytokine Induction as a Target for ASA404 221
2.3 ASA404 Combination Treatment in Mice 223
3 Clinical Development of ASA404 223
3.1 Biomarkers 225
4 Perspective 226
References 227
Vascular Disruptive Agents in Combination with Radiotherapy 232
1 Introduction 232
2 Vascular Effects of Radiation 233
3 Rationale for Combining VDAs and Radiotherapy 234
4 Tubulin-Binding VDAs and Radiotherapy 236
4.1 Combretastatin A4 Phosphate 237
4.2 Other Combretastatins 239
4.3 ZD6126 240
5 Flavonoid VDAs and Radiotherapy 240
5.1 Flavone Acetic Acid 241
5.2 5,6-Dimethylxanthenone-4-Acetic Acid 241
6 Hyperthermia, VDAs and Radiotherapy 242
7 Other Novel Agents in Combination with VDAs and Radiotherapy 244
7.1 Bioreductive Agents 244
7.2 Nitric Oxide Synthase Inhibition 244
7.3 Other Targeted Therapies 245
8 Clinical Trials of Combined VDAs and Radiotherapy 246
9 Conclusions 246
Index 252