Drug Management of Prostate Cancer (eBook)

Preface 6
Contents 8
Contributors 12
Chapter 1: Cell Biology of Prostate Cancer and Molecular Targets 20
Introduction 20
AR Axis 21
AR Antagonists 24
Inhibitors of Androgen Synthesis 24
AR Chaperone Inhibitors 24
Regulation of Apoptosis 25
Bcl-2 25
CLU 27
Hsp27 28
Signal Transduction Pathways 28
IGF and IGF-1R in CaP Progression 28
IGFBPs and CRPC 30
Phosphatidylinositol 3-Kinase-Mediated Survival Signaling in CaP 31
Angiogenesis 31
Inflammation 32
Bone Metastases 33
References 34
Part I: Hormone Therapy 44
Chapter 2: Luteinizing Hormone-Releasing Hormone and Its Agonistic, Antagonistic, and Targeted Cytotoxic Analogs in Prostate Cancer 45
Introduction 45
Agonists of LHRH 46
Principles of Oncological and Gynecological Use of LHRH-1 Agonists 47
Sustained Delivery Systems for LHRH Analogs 47
Antagonistic Analogs of LHRH 47
Principles of Gynecological and Oncological Use of LHRH Antagonists 48
Effects on the Pituitary LHRH Receptors 48
Clinical Findings 49
Receptors for LHRH Type I on Tumors 50
Direct Effects of LHRH Analogs on Tumors 50
Mechanism of Action of LHRH-I and Its Analogs 50
Clinical Applications of LHRH Antagonists 50
Use of LHRH Antagonists in BPH 51
Targeted Cytotoxic LHRH Analogs 51
LHRH Agonists in Therapy of Prostate Cancer 52
Use of LHRH Antagonists in Prostate Cancer 52
Use of Cytotoxic LHRH Analogs in Prostate Cancer 53
Side Effects 54
References 54
Chapter 3: Nuclear Receptor Coregulators: Promising Therapeutic Targets for the Treatment of Prostate Cancer 58
Introduction 58
Androgens, the Androgen Receptor, and Prostate Cancer 59
Androgens: Synthesis and Metabolites 59
Basic Mechanism of Androgen Action 59
The Androgen Receptor: Structure and Function 60
Clinical Relevance and Therapeutic Potential of the AR Signaling Axis in CaP 61
Clinical Relevance and Therapeutic Potential of Coregulators in CaP 62
Potential Approaches to Target Coregulators in CaP 64
Targeting Coregulator Expression 64
Targeting Coregulator Activity 64
Conclusions and Future Perspectives 65
References 65
Chapter 4: Androgens and Prostate Cancer 69
Introduction 69
Androgen and the Prostate 69
Biosynthesis and Metabolism of Androgens 69
Androgen Action on the Prostate 70
Androgen and Prostate Cancer 71
Testosterone Replacement Therapy and the Risk of Prostate Cancer 72
Testosterone Replacement Therapy Following Treatment for Prostate Cancer 73
Conclusion 74
References 74
Chapter 5: Androgen Receptor Biology in Prostate Cancer 76
AR Structure 77
Alterations of the Androgen Receptor in Prostate Cancer 78
AR Gene Amplification 78
AR Mutations 78
Posttranslational Modification of AR 79
Ligand Availability 80
AR Coregulators 80
Summary 81
References 81
Chapter 6: Androgen Receptor Antagonists 86
Steroidal and Nonsteroidal AR Antagonists 86
Mechanisms of AR Antagonist Action 87
AR Activation by Agonist Binding 87
Structural Changes in AR Mediated by Antagonist Binding 88
Role of Transcriptional Corepressors in AR Antagonist Action 89
Clinical Applications of AR Antagonists in CaP 90
AR Antagonist Monotherapy in Previously Untreated Patients 90
Combined Castration and AR Antagonist Therapy (Combined Androgen Blockade, CAB) 91
AR Antagonist Withdrawal Responses 91
AR Antagonists in CRPC 91
Mechanism Mediating AR Reactivation and Resistance to AR Antagonists in CRPC 92
Increased AR Expression 92
Expression of Antagonist Activated Mutant ARs 92
Increased Intratumoral Androgen Synthesis 92
Altered Expression of Transcriptional Coactivator Versus Corepressor Proteins 92
Enhanced Responses to Low Androgen Levels Mediated by Activation of Kinase Signaling Pathways 93
New AR Antagonists and Future Directions 93
References 93
Chapter 7: 5-Alpha Reductase Inhibitors in Prostate Cancer 97
Introduction 97
Androgens and Androgen Receptor 98
Conversion of Testosterone to DHT: 5-Alpha Reductase 98
The Role of 5-Alpha Reductase in the Nonmalignant Disease of the Prostate 98
5-Alpha Reductase and Cancer 99
5-Alpha Reductase Inhibitors 99
Clinical Studies with 5-Alpha Reductase Inhibitors in Prostate Cancer 100
References 101
Chapter 8: Adrenal Androgen Synthesis Inhibitor Therapies in Castration-Resistant Prostate Cancer 104
Introduction 104
The Role of Androgens 105
Initial Therapy for Advanced Prostate Cancer: Orchiectomy and GnRH/LHRH Analogs 105
Second-Line Therapies for Advanced Prostate Cancer: Anti-Androgens and Anti-androgen-Withdrawal 105
Progressive Disease: Mechanisms 106
Adrenal Androgen Synthesis Inhibitors 106
Adrenalectomy 106
Corticosteroids 106
Aminoglutethimide 107
Ketoconazole 109
Abiraterone Acetate 110
Alternative CYP17 Inhibitors 111
Estrogens and Progestins 111
Progestins 112
Conclusion 112
References 112
Chapter 9: Androgen Deprivation Therapy 114
Introduction 114
Androgen Deprivation Therapy 114
Timing of ADT 116
Androgen Deprivation Therapy, AR Antagonist, or Both? 117
Intermittent Androgen Deprivation 117
Genetic Determinants of Response to Androgen Deprivation 118
Conclusions 119
References 119
Chapter 10: Pharmacogenetics of the Androgen Metabolic Pathway 121
Androgens and Prostate Cancer 121
Prostate Cancer and Androgen Therapy and Prevention 122
Treatment of Prostate Cancer 122
Prevention of Prostate Cancer 123
Genes and Polymorphisms in the Androgen Pathway in Prostate Cancer 123
Androgen Receptor 123
The Steroid 5a-Reductase Family 124
Aromatase (CYP19A1) 126
Other Genes 126
Gene Fusions 128
Pharmacogenetics of Prostate Cancer 128
Conclusions 129
References 130
Part II: Chemotherapy 134
Chapter 11: Mitoxantrone 135
Introduction 135
Mechanism of Action 135
Pharmacological Considerations 136
Distribution 136
Metabolism 136
Excretion 136
Drug Interactions 136
Safety and Precautions 136
Dosing and Administration 138
Cumulative Dose Limits 138
Dosage in Renal Impairment 138
Dosage in Hepatic Impairment 138
Efficacy 139
Place in Therapy 139
Conclusions 140
References 140
Chapter 12: Docetaxel 142
Introduction 142
Initial Studies of Taxane-Based Therapy in Prostate Cancer 143
TAX 327 144
SWOG 99-16 145
Clinical Implications of TAX 327 and SWOG 99-16 146
Optimal Timing of Chemotherapy 146
Future Directions in Taxane-Combination Therapy 147
Antiangiogenesis Agents 147
Calcitriol Combination Therapy 148
Bone-Targeted Therapies 149
Vaccine-Taxane Therapy 150
Docetaxel and Prostatectomy 151
Docetaxel and Radiation Therapy 151
Conclusions 152
References 152
Chapter 13: Beyond Docetaxel: Emerging Agents in the Treatment of Advanced Prostate Cancer 156
Introduction 156
PI3 Kinase/Akt Pathways 156
mTOR Inhibition 157
Hsp90 Pathway 157
Insulin-Like Growth Factor Pathway 158
Histone Deacetylase Inhibitors 158
Conclusion 159
References 159
Chapter 14: Platinum Agents in Prostate Cancer 161
Introduction 161
Neuroendocrine Differentiation in Prostate Cancer 161
First-Line Platinum Chemotherapy for Prostate Cancer 163
Single-Agent Cisplatin and Carboplatin 163
Multiagent Regimens with Cisplatin and Carboplatin 164
New Platinum Drugs 165
Platinum Drugs as Second-Line Therapy for CRPC 166
Conclusion 166
References 167
Chapter 15: Clinical Pharmacology and Pharmacogenetics of Chemotherapy in Prostate Cancer 170
Introduction 170
Docetaxel 170
Mechanism of Action 170
Pharmacokinetics, Drug Distribution, and Pharmacodynamic Determinants 171
Nongenetic Sources of Variability in Docetaxel Pharmacology 171
Docetaxel Pharmacogenetics 173
CYP3A4 and CYP3A5 173
The ABCB1, ABCC2, ABCG2, and OATP1B3 Active Transporters of Docetaxel 174
Other Docetaxel Pharmacogenetics Studies 175
Mitoxantrone 175
Mechanism of Action 175
Pharmacokinetics, Drug Distribution, and Pharmacodynamic Determinants 175
Nongenetic Sources of Variability in Pharmacology 176
Pharmacogenetics 176
Estramustine 176
Mechanism of Action 176
Pharmacokinetics, Drug Distribution, and Pharmacodynamic Determinants 177
Nongenetic Sources of Variability in Pharmacology 177
Pharmacogenetics 177
Satraplatin 178
Mechanism of Action 178
Pharmacokinetics, Drug Distribution, and Pharmacodynamic Determininants 178
Nongenetic Sources of Variability in Pharmacology 179
Conclusion 179
References 179
Chapter 16: Microtubule Targeting Agents 185
Introduction 185
The Microtubule Cytoskeleton: Structure, Function, and the Importance of Microtubule Dynamics 185
Microtubule-Depolymerizing Agents 186
The Vinca Alkaloids 187
The Colchicine Class 187
Colchicine-Like Compounds 188
Peptides and Depsipeptides 189
The Mechanism of Action of Paclitaxel and Other Microtubule-Stabilizing Compounds 189
The Interaction of Paclitaxel and Microtubules 190
Nontaxane Microtubule-Stabilizing Drugs 190
The Role of Microtubule Stability and Dynamics in Drug Sensitivity 191
Resistance to Microtubule-Stabilizing Agents 192
Role of Microtubule Targeting Agents in the Treatment of Castration-Resistant Prostate Cancer 192
Epothilones in Castration-Resistant Prostate Cancer 192
Preclinical Data 193
Phase I Clinical Trials of the Epothilones 193
Phase II Clinical Trials of the Epothilones for CRPC 194
Cabazitaxel, a Novel Taxane for the Treatment of Advanced CRPC 196
Conclusion 197
References 197
Part III: Angiogenesis 201
Chapter 17: Principles of Antiangiogenic Therapy 202
Introduction 202
Mechanisms of the Angiogenic Process 203
Angiogenic Switch and Regulatory Proteins 203
Endogenous Inhibitors of Angiogenesis 204
Angiogenesis and Prostate Cancer 204
Antiangiogenic Therapy: Rationale and Classification 206
Rationale 206
Classification of Antiangiogenic Agents 206
Combination Therapies 207
Surrogate Markers of Antiangiogenic Therapy 207
Resistance to Antiangiogenic Therapy 207
Conclusion 208
References 208
Chapter 18: Bevacizumab in Advanced Prostate Cancer 211
Mechanism of Angiogenesis 211
Rationale for Targeting the Angiogenesis Pathway in Prostate Cancer 213
VEGF Targeted Inhibition 213
The Clinical Role of Bevacizumab in Prostate Cancer 213
Preclinical Data 213
Success of Bevacizumab in Cancer 214
Clinical Trials in Castration-Resistant Prostate Cancer 214
Bevacizumab in Castrate-Sensitive Prostate Cancer 216
Future Directions 217
References 217
Chapter 19: Thalidomide and Analogs 219
Introduction 219
Thalidomide as a Single Agent 220
Thalidomide in Combination Therapy 221
Thalidomide Analogs 224
Lenalidomide as a Single Agent 224
Lenalidomide in Combination Therapy 225
Summary 225
References 226
Chapter 20: Investigational Angiogenesis Inhibitors 228
Introduction 228
Evidence for the Role of Angiogenesis in Prostate Cancer 228
Investigational Angiogenesis Inhibitors 229
Targeting VEGF and VEGF-Receptor (VEGF-R) Family 230
Targeting Receptor Tyrosine Kinases Involved in Angiogenesis 231
Targeting the Extracellular Matrix, Cytokines, and Cell–Matrix Adhesion 232
Conclusions 232
References 233
Chapter 21: Pharmacogenetics of Angiogenesis 236
Introduction 236
Genetic Variants of VEGF Gene and Prostate Cancer 237
Genetic Variants of Endostatin Gene and Prostate Cancer 240
Genetic Variants of HIF Gene and Prostate Cancer 241
Genetic Variants of PDGF and PDGFR Gene and Prostate Cancer 241
Genetic Variants of MMP and TNF Gene and Prostate Cancer 243
Conclusions 243
References 244
Part IV: Bone Metastasis 246
Chapter 22: Pathophysiology of Prostate Cancer Bone Metastasis 247
Introduction 247
Bone Biology 247
Bone Remodeling 249
Osteoblastic Bone Metastases 249
Osteoclastic Bone Metastases 250
Summary 252
References 253
Chapter 23: Radiopharmaceuticals 257
Introduction 257
Clinical Manifestations of Bone Metastases 258
Physical Properties and Mechanisms of Targeting of Bone-Targeted Radiopharmaceuticals 259
Current Guidelines 259
Current Indications and Contraindications for Radionuclide Therapy 260
Overview of Randomized and Repeat-Dosing Studies with 89Strontium 260
Overview of Randomized and Repeat-Dose Studies with 153Samarium-EDTMP 262
223Radium: An Isotope in Current Development 264
Comparison Trials Using Various Radiopharmaceuticals 264
Combinations of Radiopharmaceuticals and Chemotherapy 266
Current Utilization of Radiopharmaceuticals 267
References 267
Chapter 24: Bisphosphonates for Prevention and Treatment of Bone Metastases 269
Normal Bone Physiology 269
Pathophysiology of Osteoblastic Bone Metastases 269
Clinical Manifestations of Bone Metastases 270
Bisphosphonates 270
Bisphosphonates in Metastatic Bone Disease 270
Bisphosphonates in the Treatment of Castration-Resistant Prostate Cancer 271
Bisphosphonates in the Treatment of Androgen-Sensitive Prostate Cancer 272
Bisphosphonates for the Prevention of Bone Metastases 272
Bisphosphonates: Safety 273
Future Directions in Bone-Targeted Therapy for Prostate Cancer 274
Denosumab: RANK-Ligand Inhibitor in Current Clinical Trials 274
Prevention of Osteoporosis and Fractures During ADT 275
Conclusion 275
References 276
Chapter 25: Endothelin Receptors as Therapeutic Targets in Castration-Resistant Prostate Cancer 278
The Endothelin Axis 278
Endothelin-1 in Prostate Cancer 279
Endothelin Receptors in Prostate Cancer 279
Effects of Endothelin on Cancer Cells In Vitro 280
Endothelin Axis and Bone Metastases 281
ET Axis and Pain 281
Atrasentan (ABT-627) 282
Atrasentan: Phase I Trials 282
Atrasentan: Phase II Trials in Prostate Cancer 282
M96-500 282
M96-594 283
Atrasentan: Phase III Trials in Prostate Cancer 283
M00-211 283
M00-244 284
Ongoing Phase III Trial 285
Summary 285
Conclusions 285
References 285
Chapter 26: Calcitriol and Vitamin D Analogs 288
Epidemiology of Vitamin D and Prostate Cancer 288
Prostate Cancer Risk 288
Prostate Cancer Outcomes 289
Mechanisms of Antineoplastic Activity in Preclinical Systems 289
Vitamin D Signaling 289
Spectrum of Activity 290
Mechanisms of Antineoplastic Activity 290
Differentiation and Inhibition of Proliferation 290
Apoptosis 291
Angiogenesis and Invasiveness 291
Preclinical Studies of Calcitriol and Vitamin D Analogs in Combination with Other Antineoplastic Agents 291
Steroids 291
Cytotoxic Chemotherapy 292
Retinoid Receptor Ligands 292
Tamoxifen 292
Nonsteroidal Anti-inflammatory Agents (NSAIDs) 292
Radiation 292
Clinical Trials of Calcitriol and Vitamin D Analogs 292
Phase I Studies 293
Alternate Day Dosing 293
Weekly Dosing 293
Dosing 3 of Every 7 Days 293
Dosing Every 3 Weeks 294
Phase II Studies 294
Single Agent Calcitriol 294
Combination with Docetaxel 294
Combinations with Carboplatin 295
Combination with Mitoxantrone 295
Other Calcitriol Analogs 295
Conclusions 296
References 296
Part V: Immunotherapy 304
Chapter 27: Cancer Immunology, Immunotherapeutics, and Vaccine Approaches 305
Rationale for Vaccines in the Treatment of Prostate Cancer 305
Tumor-Associated Antigens As Targets of Immunotherapy 306
Enhancing Antigen Presentation 306
Vaccines as Part of Combination Therapy for Prostate Cancer 307
Androgen-Deprivation Therapy 307
Radiation Therapy 307
Combination Chemotherapy 307
Sequential Chemotherapy 308
Anti-CTLA-4 308
Vaccine Approaches 308
Vector-Based Vaccines 308
PSA-TRICOM 310
Antigen-Presenting Cell Vaccines: Sipuleucel-T 311
Whole Tumor-Cell Vaccines 312
GVAX 312
ONY-P1 314
Future Directions 314
Regulatory T-Cell Depletion 314
Evaluating Vaccines in the Clinical Setting 314
References 315
Chapter 28: Sipuleucel-T: Autologous Cellular Immunotherapy for Metastatic Castration-Resistant Prostate Cancer 320
Introduction 320
Sipuleucel-T Cellular Immunotherapy 321
Clinical Efficacy of Sipuleucel-T 322
Phase I/II Studies 322
Completed Phase III Clinical Studies in CRPC 322
D9901 Study 322
D9902A Study 323
D9902B Study 324
Developmental History of Sipuleucel-T in Metastatic CRPC 324
Ongoing Randomized Study 325
Safety and Tolerability 325
Discussion 325
References 325
Chapter 29: GM-CSF Gene-Transduced Prostate Cancer Vaccines: GVAX 327
Introduction 327
Preclinical Rationale for GM-CSF Genetically Transduced Vaccines 328
Clinical Development of GM-CSF Genetically Transduced Vaccines 330
Expansion of Clinical Trials of GVAX from Academic Investigation 332
Phase II: G-9803 and G-0010 332
Safety Profile 333
Phase III: Vital-1 and Vital-2 333
Tumor Tolerance and Cancer Vaccine Resistance: New Frontiers 335
Conclusions, Observations, and Future Directions 337
References 338
Chapter 30: CTLA-4 Blockade for Prostate Cancer Treatment 341
Introduction 341
Preclinical 341
Clinical 342
Combination Therapy 343
Toxicity (and Response) 344
Future Directions 344
Conclusions 345
References 345
Part VI: Prevention 347
Chapter 31: Prostate Cancer Chemoprevention Strategies 348
Introduction 349
Carcinogenesis 349
Chemoprevention 349
Prostate Cancer Prevention Clinical Trials 349
Chemoprevention Agent Development 349
Trial Endpoints 349
Study Cohorts 350
HGPIN Cohort 352
Positive Family History Cohort 353
Elevated PSA, Negative Biopsy Cohort 353
Active Surveillance Cohort 353
Preprostatectomy Cohort 353
Chemoprevention Clinical Trial Program 353
Phase III Prostate Cancer Chemoprevention Trials 354
The Prostate Cancer Prevention Trial 354
Overview 354
Results 355
Adverse Events 355
Does Finasteride Make the Grade? 355
PCPT: Conclusions 356
The Reduction by Dutasteride of Prostate Cancer Events Trial 356
The Selenium and Vitamin E Cancer Prevention Trial 357
Conclusions 357
References 358
Chapter 32: Diet and Prostate Cancer Incidence, Recurrence, and Progression Risk 360
Background 360
Methods 361
Diet and Prostate Cancer 361
Vegetables and Fruits 362
Legumes and Soy 362
Cruciferous Vegetables 362
Tomatoes and Lycopene 362
Vitamin E 363
Selenium 363
Milk, Dairy, and Calcium 364
Meat, Poultry, Fat, and Prostate Cancer 364
Red and Processed Meat 364
Poultry 365
Biological Mechanisms for Meat and Poultry 365
Fish and Marine Omega-3 Fatty Acids 366
Diet and Prostate Cancer Progression and Survival 367
Conclusions 367
References 367
Chapter 33: Inflammation as a Target in Prostate Cancer 371
Chronic Inflammation of the Prostate 371
Possible Causes of Prostatic Inflammation 372
Infectious Agents 372
Hormones 372
Dietary Factors 373
Prostatic and Urinary Factors 373
Inflammatory Genes in Prostate Cancer 373
RNASEL 373
Prostate-Derived Factor 374
Macrophage Scavenger Receptor (MSR1) 374
Interleukins 374
Toll-Like Receptors 375
Chronic Inflammation in the Development of Prostate Cancer 375
Cytokines and Growth Factors 375
Oxidative Stress 376
Cyclooxygenase-2 377
Inflammation in Metastasis 378
Targeting Inflammation in the Management of Prostate Cancer 378
Conclusion 379
References 379
Part VII: Drug Development 383
Chapter 34: Challenges for the Development of New Agents in Prostate Cancer 384
Introduction 384
Defining Appropriate Clinical Endpoints Based on Stage of Development 385
Screening for Antitumor Effect: “The Phase II Setting” 385
Objective Response: How Defined? 385
Time-to-Event End Points 385
Challenges in Using Time-to-Event Endpoints in CRPC 385
The Phase III Setting 386
Patient-Reported Outcomes 386
Composite Endpoints 387
Use of Alternative Clinical Endpoints 387
Biomarkers 387
PSA 387
PSA Response 388
PSA Progression 388
Limitations of PSA Based End-Points 389
Biochemical Markers of Bone Turnover 389
Circulating Tumor Cells 390
Conclusions 390
References 390
Chapter 35: FDA Approval of Prostate Cancer Treatments 393
Introduction 393
General FDA Approval Process for Anticancer Drugs 394
Approved Prostate Cancer Treatments 395
Hormonal Agents 395
Supportive Agents 395
Cytotoxic Agents 395
Estramustine 396
Mitoxantrone 396
Docetaxel 396
Challenges in Approval of Prostate Cancer Treatments 397
Summary 398
Footnotes 398
References 398
Chapter 36: Applications of Proteomics in Prostate Cancer 400
Introduction 400
Cancer Biomarkers Overview 400
Current Status of Tissue-Based Protein Biomarkers 401
Tissue-Based Diagnostic Markers 401
Tissue-Based Prognostic Markers 401
Current Status of Blood-Based Protein Biomarkers 403
PSA as an Example of a Widely Used Blood-Based Biomarker 403
Overview of Proteomic Technologies 404
Sample Preparation 404
Protein/Peptide Separation 404
Protein Identification and Protein Quantification 405
Examples of Proteomic Applications for Prostate Cancer 406
Summary 407
References 407
Index 411