Vascular-Targeted Therapies in Oncology

Preface xiii

List of Contributors xv

1 Tumor Vasculature: a Target for Anticancer Therapies 1
Dietmar W. Siemann

1.1 Introduction 1

1.2 Tumor vasculature 1

1.3 Impact of tumor microenvironments on cancer management 2

1.4 Vascular-targeting therapies 3

1.5 Combinations with conventional anticancer therapies 4

1.6 Combinations of antiangiogenic and vascular-disrupting agents 5

1.7 Conclusions 5

Acknowledgments 6

References 6

2 Abnormal Microvasculature and Defective Microcirculatory Function in Solid Tumors 9
Peter Vaupel

2.1 Introduction 9

2.2 Basic principles of blood vessel formation in tumors 10

2.3 Tumor lymphangiogenesis 13

2.4 Tumor vascularity and blood fl ow 13

2.5 Volume and composition of the tumor interstitial space 17

2.6 Fluid pressure and convective currents in the interstitial space of tumors 18

2.7 Evidence, characterization and pathogenesis of tumor hypoxia 18

2.8 Tumor pH 23

2.9 The ‘crucial Ps’ characterizing the hostile metabolic microenvironment of solid tumors 25

Acknowledgment 27

References 27

3 The Role of Microvasculature in Metastasis Formation 31
Oliver Stoeltzing and Lee M. Ellis

3.1 Introduction 31

3.2 Regulators of angiogenesis in solid tumors 34

3.3 Angiogenesis and metastasis formation 47

3.4 Summary 53

References 53

4 Development of Agents that Selectively Disrupt Tumor Vasculature: a Historical Perspective 63
David J. Chaplin and Sally A. Hill

4.1 Introduction 63

4.2 Early history 65

4.3 Formulation of the VDA concept 67

4.4 Effects of vascular occlusion on tumor cell survival 68

4.5 Rational development of VDA therapeutics 68

4.6 Development of small-molecule VDAs 70

4.7 Combretastatin A4 phosphate 73

4.8 The viable rim 76

4.9 Conclusions 76

References 77

5 Morphologic Manifestations of Vascular-Disrupting Agents in Preclinical Models 81
Mumtaz V. Rojiani and Amyn M. Rojiani

5.1 Introduction 82

5.2 Animal models 82

5.3 Morphologic and morphometric analysis 84

5.4 Effects of treatment 85

Acknowledgments 92

References 92

6 Molecular Recognition of the Colchicine Binding Site as a Design Paradigm for the Discovery and Development of Vascular Disrupting Agents 95
Kevin G. Pinney

6.1 Introductory comments 95

6.2 Colchicine binding site on tubulin 96

6.3 Brief overview of tubulin biology 97

6.4 Small-molecule inhibitors of tubulin assembly 100

6.5 Design paradigm for small-molecule vascular disrupting agents 105

6.6 Concluding remarks 113

Acknowledgments 114

References 114

7 Combined Modality Approaches Using Vasculature disrupting Agents 123
Wenyin Shi, Michael R. Horsman and Dietmar W. Siemann

7.1 Tumor vasculature 123

7.2 Vascular-disrupting strategies 124

7.3 VDAs and chemotherapy 125

7.4 VDAs and radiation therapy 128

7.5 VDAs and antiangiogenic agents 131

7.6 Summary 131

Acknowledgments 132

References 132

8 Vasculature-targeting Therapies and Hyperthermia 137
Michael R. Horsman and Rumi Murata

8.1 Introduction 137

8.2 Enhancing hyperthermia 140

8.3 Enhancing thermoradiotherapy 148

8.4 Conclusions and clinical relevance 151

Acknowledgments 152

References 152

9 Flavones and Xanthenones as Vascular-disrupting Agents 159
Bronwyn G. Siim and Bruce C. Baguley

9.1 Development of FAA and DMXAA 159

9.2 Antivascular activity of FAA and DMXAA 161

9.3 Cytokine induction by FAA and DMXAA 162

9.4 Molecular target 163

9.5 Preclinical studies: DMXAA as a single agent 164

9.6 Preclinical studies: combination treatments 165

9.7 Species differences 169

9.8 Clinical studies 171

References 172

10 Targeting Inside-Out Phospholipids on Tumor Blood Vessels in Pancreatic Cancer 179
Adam W. Beck, Rolf Brekken and Philip E. Thorpe

10.1 Vascular targeting 179

10.2 Pancreatic cancer: the clinical need 180

10.3 Phosphatidylserine 181

10.4 Proof of concept studies 183

10.5 Combined treatment with 3G4 and gemcitabine in a pancreatic cancer model 185

10.6 Mechanism of action 188

10.7 Conclusion 191

References 191

11 Cadherin Antagonists as Vasculature-targeting Agents 195
Orest Blaschuk and Tracey M. Rowlands

11.1 Pericytes as regulators of blood vessel stability 195

11.2 Cadherins 196

11.3 Cadherins and the vasculature 197

11.4 Tumor vasculature 199

11.5 Manipulation of the tumor vasculature with cadherin antagonists 200

11.6 Summary and future directions 201

Acknowledgment 201

References 201

12 Alphastatin: a Pluripotent Inhibitor of Activated Endothelial Cells 205
Carolyn A. Staton and Claire Lewis

12.1 Introduction 205

12.2 Discovery of alphastatin 207

12.3 Development of alphastatin 210

12.4 Conclusions 218

References 218

13 Cationic Lipid Complexes to Target Tumor Endothelium 221
Uwe Michaelis and Michael Teifel

13.1 Introduction 221

13.2 Tumor vascular targeting by cationic liposomes 222

13.3 Potential targets for cationic lipid complexes on tumor endothelial cells 225

13.4 Cationic liposomes as drug carriers 227

13.5 Side-effects of intravenously administered cationic lipid complexes 230

13.6 Preclinical data 232

13.7 Clinical data 238

13.8 Conclusion 239

Acknowledgments 240

References 240

14 Development of Vasculature-targeting Cancer Gene Therapy 247
Graeme J. Dougherty, Peter D. Davis and Shona T. Dougherty

14.1 Introduction 247

14.2 Advantages of tumor vasculature as a target in cancer gene therapy 248

14.3 Genes of value in vascular-targeted cancer gene therapy 249

14.4 Targeting gene therapy to tumor vasculature 249

14.5 Concluding remarks 256

Acknowledgment 256

References 257

15 Vasculature-disrupting Strategies Combined with Bacterial Spores Targeting Hypoxic Regions of Solid Tumors 261
G-One Ahn and J. Martin Brown

15.1 Hypoxia and necrosis as a selective target for cancer therapy 261

15.2 Use of Clostridia as hypoxia/necrotic selective cancer therapy 262

15.3 Advantage of CDEPT over ADEPT and GDEPT 265

15.4 Combination of CDEPT with vascular-disrupting agents 267

15.5 Clinical signifi cance 272

References 273

16 Imaging the Effects of Vasculature-targeting Agents 277
Susan M. Galbraith

16.1 Introduction 277

16.2 Methods for imaging tissue blood fl ow rate 278

16.3 Central volume theorem 279

16.4 Kety model 280

16.5 Fraction of cardiac output or ‘fi rst-pass’ methods 286

16.6 Color Doppler ultrasonography 286

16.7 Imaging hypoxia 287

16.8 Imaging glucose metabolism 288

16.9 Preclinical experience of imaging vascular-disrupting agents 290

16.10 Clinical experience of imaging vascular-disrupting agents 293

16.11 Conclusions 296

References 298

17 Clinical Progress in Tumor Vasculature-disrupting Therapies 305
Andrew M. Gaya and Gordon J. S. Rustin

17.1 Introduction 305

17.2 Potential clinical advantages of vascular-disrupting agents 306

17.3 Biological (ligand-directed) VDAs 306

17.4 Small-molecule VDAs 307

17.5 Potential surrogate markers of CA4P activity 314

17.6 Combination therapy with VDAs 317

17.7 VDAs in non-malignant diseases 318

17.8 Conclusions 319

References 319

18 Use of Vasculature-disrupting Agents in Non-Oncology Indications 323
Joseph C. Randall and Scott L. Young

18.1 Background 323

18.2 Age-related macular degeneration (AMD) 325

18.3 Myopic macular degeneration 327

18.4 Retinopathy of prematurity 330

18.5 Proliferative diabetic retinopathy 331

18.6 Pediatric hemangiomas 332

18.7 Arthritis 333

18.8 Psoriasis 334

18.9 Conclusions 336

References 336

Index 341