Renal Cell Carcinoma (eBook)

Preface 5
Contents 9
Contributors 12
Chapter 1 17
Targeted Therapy for Metastatic Renal Cell Carcinoma: Overview 17
1 Background 17
2 VHL Gene: Role in Renal Cell Carcinoma 18
3 Management of Advanced Renal Cell Carcinoma: Historical 20
4 Prognostic Factors in Renal Cell Carcinoma 20
5 Bevacizumab 21
6 Sorafenib 22
7 Sunitinib 23
8 mTOR Inhibitors: Temsirolimus 24
9 Summary 25
References 27
Chapter 2 29
Molecular Genetics in Inherited Renal Cell Carcinoma: Identification of Targets in the Hereditary Syndromes 29
1 Introduction 30
2 Identification of the VHL Gene 30
2.1 von Hippel–Lindau 31
2.1.1 Sporadic RCC 33
2.1.2 Cystic Lesions in VHL 33
2.2 Function of the VHL Gene 35
3 Hereditary Papillary Renal Carcinoma 36
3.1 Identification of the Gene for HPRC 37
4 Birt–Hogg–Dubé 37
4.1 Identification of the BHD Gene 39
5 Hereditary Leiomyomatosis Renal Cell Carcinoma 40
6 Treatment 41
6.1 Localized Disease 41
6.2 Metastatic Disease 42
6.3 Targeting VHL 42
6.4 Altering the c-MET Pathway 44
6.5 HSP-90 Inhibition 44
7 Conclusion 45
References 45
Chapter 3 50
Molecular Targets in Renal Tumors: Pathologic Assessment 50
1 Histological Classification of RCCs 50
1.1 Renal Cell Carcinoma, Clear Cell Type (Clear Cell RCC) 51
1.2 Multilocular Cystic Renal Cell Carcinoma 52
1.3 Renal Cell Carcinoma, Papillary Type (Papillary RCC) 53
1.4 Renal Cell Carcinoma, Chromophobe Type (Chromophobe RCC) 53
1.5 Carcinoma of the Collecting Duct of Bellini (Collecting Duct Carcinoma) 55
1.6 Renal Medullary Carcinoma 55
1.7 RCCs Associated with Xp11.2 Translocation/TFE3 Gene Fusion 55
1.8 Mucinous Tubular and Spindle Cell Carcinoma 56
1.9 RCC Associated with Neuroblastoma 57
1.10 Renal Cell Carcinoma, Unclassified Type 57
1.11 Papillary Adenoma 57
1.12 Renal Oncocytoma 58
2 Histological Prognostic Factors for Renal Cell Carcinoma 58
2.1 Histological Subtypes 59
2.2 Fuhrman Grading System 59
2.3 Sarcomatoid Renal Cell Carcinoma 59
2.4 Tumor Necrosis 60
2.5 Invasion of Urinary Collecting System 60
2.6 Microvascular Invasion 60
2.7 Completeness of Tumor Resection 61
3 Handling of RCC Specimens 61
4 Summary 61
References 62
Chapter 4 64
Interferons and Interleukin-2: Molecular Basis of Activity and Therapeutic Results 64
1 Introduction 64
2 IFNs: Mechanisms of Actions 66
2.1 Signaling 66
2.2 Angiogenesis Inhibition 67
2.3 Immune Modulation 67
2.4 Apoptosis 68
2.5 Summary 69
3 IL-2: Mechanism of Action 69
3.1 Preclinical Studies of IL-2: In Vitro Studies 69
3.2 Expression and Function of IL-2 Receptor Subunits 70
3.3 Helper Role of IL-2 in T1-Type Cell-MediatedImmunity and the Reversal of Anergy 71
3.4 Characterization of IL-2 Monotherapyin Mouse Tumor Models 73
3.5 Characterization of LAK Cells 73
3.6 IL-2 In Vivo Impact on Defined T Cell Populations 74
3.7 Summary: Preclinical Studies of IL-2 76
4 IFNs: Clinical Effects 77
5 IL-2 Clinical Effects 79
6 Perspective 82
References 83
Chapter 5 94
The Molecular Biology of Kidney Cancer and Its Clinical Translation into Treatment Strategies 94
1 Introduction 94
2 von Hippel–Lindau Disease 95
3 VHL mutations in Sporadic Cancers 95
4 The VHL Protein 96
5 VHL and the Biology of Clear Cell Renal Carcinoma 97
6 Validation of HIF as a Therapeutic Target in Renal Carcinoma 98
6.1 Targets that Affect HIFAlpha Accumulation 99
6.2 HIF-Responsive Targets 99
7 VEGF-Targeted Therapy in RCC 100
8 VEGF Neutralizing Antibody Therapy in RCC 101
9 Multitargeted Tyrosine Kinase Inhibition in RCC 102
9.1 Sunitinib 103
9.2 Sorafenib 104
10 mTOR Inhibition in RCC 105
11 Summary 106
References 106
Chapter 6 113
VEGF: Biologic Aspects and Clinical Approaches 113
1 Introduction 113
2 Biologic Consequences of VHL Gene Inactivation in RCC 114
3 The VEGF Pathway in RCC 115
3.1 VEGF – Basic Principles 115
3.1.1 Protein Structure and Isoforms 116
3.2 Regulation of VEGF: Management at Many Levels 117
3.2.1 Cellular Sources of VEGF 117
3.2.2 VEGF: Transcriptional Regulation 118
3.2.3 VEGF: Regulation of mRNA Stability 118
3.2.4 VEGF: Translational Regulation 119
4 VEGF Function 119
5 VEGF and Cancer 121
6 Clinical Approach to VEGF Inhibition in RCC 122
6.1 Anti-VEGF Antibody (Bevacizumab) 122
6.2 VEGF-Trap 125
7 Conclusions 127
References 127
Chapter 7 133
VEGF and PDGF Receptors: Biologic Relevance and Clinical Approaches to Inhibition 133
1 Introduction 133
2 VEGF Ligands 135
3 Expression, Signal Transduction, and Function of VEGFRs 135
3.1 Vascular Endothelial Growth Factor Receptor 1 137
3.2 Vascular Endothelial Growth Factor Receptor 2 138
3.3 Vascular Endothelial Growth Factor Receptor 3 140
3.4 Neuropilins 142
3.5 Co-receptors for VEGFRs 143
3.6 Prognostic Role of VEGF–VEGFR Expression in RCC 144
4 PDGF Ligands 145
5 Role of PDGF Ligands and Receptors in Tumor Development 146
5.1 Autocrine PDGFR Signaling 146
5.2 Role of PDGF Ligands and Receptors in Angiogenesis 147
5.3 Recruitment of Tumor Fibroblasts 148
5.4 Role of PDGF Ligands and Receptors in Control of Tissue Interstitial Fluid Pressure 149
6 Perspectives and Future Directions 150
References 151
Chapter 8 164
Sunitinib and Axitinib in Renal Cell Carcinoma 164
1 Introduction 164
2 Sunitinib (SU11248) 165
2.1 Preclinical Activity of Sunitinib 165
2.2 Safety and Clinical Activity of Sunitinib: Phase I Studies 166
2.3 Efficacy and Safety of Sunitinib in Cytokine-Refractory mRCC: Phase II Studies 167
2.3.1 Efficacy 168
2.3.2 Safety 169
2.3.3 Biomarkers of Response to Sunitinib 170
2.3.4 Patient Reported Outcomes 170
2.4 Efficacy and Safety of Sunitinib as First-Line Therapy in mRCC: Pivotal Phase III Randomized Trial 171
2.5 Other Sunitinib Studies in mRCC 171
2.5.1 Sunitinib Administered in a Continuous Dosing Regimen 171
2.5.2 Sunitinib in Patients with Bevacizumab-Refractory mRCC 172
2.5.3 Combination Study of Sunitinib Plus Gefitinib 172
2.5.4 Sunitinib Expanded-Access Study 173
3 Axitinib (AG-013736) 173
3.1 Preclinical Activity of Axitinib 173
3.2 Clinical Data: Phase I Safety and Pharmacokinetics 174
3.3 Efficacy and Safety in Cytokine-Refractory mRCC: Phase II Data 174
3.3.1 Biomarkers of Response to Axitinib 175
3.4 Efficacy and Safety in Sorafenib-Refractory mRCC: Phase II Data 175
4 Discussion and Future Directions 176
References 177
Chapter 9 179
Sorafenib in Renal Cell Carcinoma 179
1 Introduction 179
2 Background 179
2.1 Molecular Structure 179
2.2 Preclinical Data 180
2.3 Molecular Targets 181
2.4 Pharmacokinetics/Pharmacodynamics 181
3 Sorafenib Approval 182
4 Sorafenib Clinical Trials in RCC 182
4.1 Phase I 185
4.2 Sorafenib Monotherapy 185
4.2.1 Phase II RDT 185
4.2.2 Phase III 186
4.2.3 Phase II Interferon Versus Sorafenib 188
4.2.4 Phase IV 190
4.3 Sorafenib Combination Studies 190
4.3.1 IFN-Alpha and Sorafenib 191
4.4 Avastin and Sorafenib 192
4.5 Temsirolimus and Sorafenib 192
5 Clinical Issues 192
5.1 Treatment-Refractory Patients 192
5.2 Treatment-Naive Patients 193
5.3 Dose Optimization 193
5.4 Biomarkers 194
5.5 Sequential TKI Therapy 195
5.6 Adjuvant and Neoadjuvant Trials 196
6 Conclusion 196
References 196
Chapter 10 200
Additional Tyrosine Kinase Inhibitors in Renal Cell Carcinoma 200
1 Introduction 200
2 Pazopanib 200
3 AZD2171 202
4 PTK787/ZK222584 202
5 Conclusion 203
References 203
Chapter 11 205
Integrin Alpha5Beta1 as a Novel Therapeutic Target in Renal Cancer 205
1 Introduction 206
2 Biology of Alpha5Beta1 in Renal Cancer 207
2.1 Gene Expression Profile of Alpha5Beta1 207
2.2 Up-Regulation of Alpha5Beta1 Gene Expression in Proliferating HUVEC 207
2.3 Effect of Volociximab on HUVEC Proliferation and Tube Formation 207
2.4 Selectivity of Volociximab 209
2.5 Effect of Volociximab on Angiogenesis in a Laser-Induced Model of CNV in Cynomolgus Monkeys 212
2.6 Expression of Alpha5Beta1 in Renal Cancer 212
2.7 Inhibition of Proliferation of RCC Cells In Vitro 215
3 Role of Platelets in Side Effects of Anti-Angiogenic Therapy 216
3.1 Role of Alpha5Beta1 in Platelet Function 216
4 Clinical Program with Volociximab 217
5 Conclusions 218
Reference 218
Chapter 12 220
Carbonic Anhydrase IX: Biology and Clinical Approaches 220
1 Introduction 220
2 The Carbonic Anhydrase Family 221
3 Discovery of CAIX 221
4 CAIX Function 222
4.1 Biology of Hypoxic Cells 222
4.2 Hypoxia and Acidosis-Induced Tumor Progression 223
4.3 Resistance to Therapy 223
4.4 Tumor Hypoxia and CAIX 223
4.5 CAIX and Acidosis 224
4.6 Summary of Function 224
5 Regulation of CAIX 224
6 CAIX Expression and RCC 225
7 CAIX and Clinical Behavior 226
7.1 Invasion and Metastasis in RCC 226
7.2 CAIX and Prognosis 226
7.3 Response to Immunotherapy 227
8 Targeting CAIX Pathway 229
8.1 CAIX Animal Model 229
8.2 G250 Monoclonal Antibody 229
8.3 G250 Nuclear Imaging 231
8.4 G250 Radioimmunotherapy 231
8.5 Chimeric G250 Monoclonal Antibody 231
8.6 Future of cG250 Radioimmunotherapy 232
8.7 cG250 Antibody-Dependent Cellular Cytotoxicity 232
8.8 Vaccine-Based Strategies 233
9 Conclusions 234
References 234
Chapter 13 239
Monoclonal Antibody G250 Recognizing Carbonic Anhydrase IX in Renal Cell Carcinoma: Biological and Clinical Studies 239
1 Introduction 240
2 Targeted Therapy with mAb G250 242
2.1 Clinical Studies with Radiolabeled Murine mAb G250 243
2.1.1 131I-mG250, Phase I Dose Escalation 243
2.1.2 131I-mG250, Phase I/II RIT 243
2.2 Clinical Studies with Radiolabeled Chimeric mAb G250 (cG250) 244
2.2.1 131I-cG250, Phase I Dose Escalation 244
2.2.2 131I-cG250 and 125I-cG250, a Dual-Label Study 245
2.2.3 131I-cG250, Phase I Activity Dose-Escalation Study 245
2.2.4 131I-cG250, Phase I RIT, Fractionated Dose 246
2.2.5 131I-cG250, Phase I/II RIT, Two High Doses 246
2.2.6 177Lu-cG250, Phase I/II RIT 248
2.3 Clinical Studies with Unmodified cG250 251
2.3.1 cG250, Phase II Immunotherapy (WX-G250) 251
2.3.2 cG250 and IL-2, Phase II Immunotherapy 252
2.3.3 cG250 and IFN, Phase II Immunotherapy 252
References 253
Chapter 14 256
Chemokines in Renal Cell Carcinoma: Implications for Tumor Angiogenesis and Metastasis 256
1 Introduction 256
2 Chemokines and Chemokine Receptors 257
3 Chemokines in Tumor Angiogenesis 257
4 Chemokines in Tumor Metastasis 261
5 Regulation of Chemokines 262
6 Targeting Chemokines 264
6.1 CXCR2 Antagonists 265
6.2 CXCR4 Antagonists 265
7 Conclusions 266
References 267
Chapter 15 273
PI3K/Akt/mTOR Pathway: A Growth and Proliferation Pathway 273
1 Molecular Biology of PI3K/Akt/mTOR Pathway 274
1.1 PI3K-Akt Activation 274
1.2 Hyperactivation of PI3K/Akt in Tumors 275
1.3 Consequences of Akt Activation 276
1.4 mTOR in Growth and Prolieration 277
1.5 Regulation Loops in the PI3K/Akt/mTOR Pathway 279
2 Clinical Activity of mTOR Inhibitors 280
2.1 Temsirolimus in Rcc 280
2.2 Everolimus in RCC 283
2.3 Patient Selection Opportunities 283
3 Future Directions for the PI3K/Akt/mTOR Pathway in RCC 285
3.1 Therapeutic Potential of Targeting the PI3K-Akt Pathway 285
3.2 Agents in Development 286
4 Conclusion 286
References 287
Chapter 16 292
EGFR and HER2: Relevance in Renal Cell Carcinoma 292
1 ErbB Receptor Family in RCC 292
2 ErB Receptor Blockade: Strategies 295
2.1 Cetuximab (C225) 295
2.2 Panitumumab (ABX-EGF) 296
2.3 Small Molecule Inhibitors 296
2.3.1 Gefitinib 296
2.3.2 Erlotinib 297
2.3.3 Lapatinib 297
3 Clinical Experience with ErbB Receptor-Targeted Therapy in RCC 298
3.1 Cetuximab Studies 298
3.2 Panitumumab 298
3.3 Gefitinib Studies 299
3.4 Erlotinib Studies 299
3.5 Lapatinib 300
4 Future Perspectives: Patient Selection and Mechanisms of Resistance 300
5 Summary 302
References 303
Chapter 17 309
Proteasome–NFkB Signaling Pathway: Relevance in RCC 309
1 Introduction 310
2 Molecular Aspects of the Proteosome Pathway 310
3 Importance of the Proteasome–NFkB Pathway in RCC 312
4 Preclinical Models Evaluating Proteasome Inhibition in RCC 314
5 Proteasome Inhibition in Advanced RCC: Clinical Data 319
6 Summary 320
References 321
Chapter 18 325
The Role of Hepatocyte Growth Factor Pathway Signaling in Renal Cell Carcinoma 325
1 Introduction 325
2 The HGF/c-Met Signaling Pathway: An Overview 326
3 The HGF/c-Met Signaling Pathway in Kidney 327
3.1 HGF Signaling in Kidney Development 327
3.2 HGF Signaling in Renal Homeostasis 328
3.3 Dysregulated HGF Signaling in RCC 329
3.3.1 HGF/c-Met Pathway Activation in HPRC Type 1 and Sporadic PRC 329
3.3.2 HGF/c-Met Signaling in Clear Cell RCC 332
4 Cancer Drug Development: Targeting the HGF/c-Met Pathway 333
References 334
Chapter 19 339
Smac/DIABLO: A Proapoptotic Molecular Target in Renal Cell Cancer 339
1 Introduction 340
2 Smac/DIABLO in the Apoptotic Pathway 341
3 Smac/DIABLO Expression as a Prognostic Marker for RCC (23) 343
4 Smac/DIABLO as a Proapoptotic Molecular Target for RCC 347
5 Concluding Remarks 348
References 348
Chapter 20 351
EphA2: A Novel Target in Renal Cell Carcinoma 351
1 EphA2 Overview 352
1.1 Eph Receptor and Ephrin Ligands 352
1.2 EphA2 352
2 Regulation of EphA2 Expression 353
2.1 EphA2 Expression and Life Cycle in Nontransformed Tissues 353
2.2 EphA2 and PTPs 354
2.3 Genetic Regulation of EphA2 355
3 Signaling Through EphA2 356
3.1 Mitogen-Activated Protein Kinase 356
3.2 Focal-Adhesion Kinase 357
4 Role of EphA2 in Cancer 357
4.1 Overexpression of EphA2 in Cancer 357
4.2 Mechanisms of EphA2 Overexpression in Cancer 358
4.3 Role(s) of EphA2 in Tumorigenesis 359
4.4 Angiogenesis 360
5 Therapeutic Approaches Targeting EphA2 361
5.1 Interventions Targeting EphA2 Activation/degradation 361
5.1.1 Anti-EphA2 Antibodies 361
5.1.2 Ephrin-A1 Fc 361
5.1.3 Peptide Mimetics 362
5.2 Interventions Targeting EphA2 Ligands 362
5.3 Gene Silencing by siRNA 362
5.4 EphA2-Based Vaccines 363
5.5 Combination Therapies Targeting EphA2 364
6 Conclusions 365
References 365
Chapter 21 371
Restoring Host Antitumoral Immunity: How Coregulatory Molecules Are Changing the Approach to the Management of Renal Cell Carcinoma 371
1 A Brief Introduction to Tumor Immunology 371
1.1 Central Tolerance 372
1.2 Peripheral Tolerance 372
1.3 Regulatory T Cells 373
1.4 Immune Surveillance 374
1.5 Immunoediting 375
1.6 T-Cell Activation 375
1.7 Signal 1: Antigen Presentation to the T Cell 376
1.8 Signal 2: Costimulation and Coinhibition 377
1.9 Signal 3: Cytokine Release 382
2 Leukocyte Dysfunction in RCC 383
2.1 Tumor-Infiltrating Leukocytes 383
2.2 T Lymphocytes in RCC 384
2.3 NK Cells in RCC 385
2.4 Neutrophils, Monocytes, and Macrophages in RCC 386
3 Clinical Aspects of Costimulation and Coinhibition in RCC 386
3.1 Classic Pathways: B7-1/2, CD28, and CTLA-4 386
3.2 Novel Pathways: Other Members of the B7/CD28 Family 390
3.3 Novel Pathways: The TNF/TNFR Family 392
4 A Model for Immune Dysfunction in RCC 392
References 393
Chapter 22 408
The Role of Gangliosides in Renal Cell Carcinoma 408
1 Gangliosides As Membrane Glycosphingolipids 409
1.1 Structure and Function 409
1.2 Gangliosides in Renal Cell Carcinoma 410
2 Gangliosides and Growth Factors Modulation 411
2.1 Modulation of Angiogenesis and VEGF Production 411
2.2 Modulation of EGFR 413
2.3 Modulating bFGF and PDGF Activity 415
2.4 Variability in Gangliosides-Induced Modulation 416
3 Using Gangliosides As Therapeutic Targets in RCC 417
3.1 Functional Role 417
3.2 Prognostic Value 417
3.3 Antiganglioside Antibodies 421
3.4 Immunization with Gangliosides 421
3.5 Difficulties in Targeting Gangliosides in RCC 422
References 423
Chapter 23 427
Tumour Necrosis Factor – Misnomer and Therapeutic Target 427
1 Introduction 427
2 TNF As a Prognostic Indicator in RCC 428
3 Intratumoural TNF: Synthesis by Tumour-Associated Macrophages 429
4 Intratumoural TNF: Synthesis by the RCC Tumour Cells Themselves 430
5 Biological Effects of TNF in the Tumour Microenvironment 430
6 TNF-Induced Tumour Gangliosides and Immune Suppression 432
6.1 Clinical Applications of TNFalpha in Cancer 433
6.2 TNFalpha As a Therapeutic Agent 433
6.3 Inhibition of Endogenous TNFalpha 435
6.4 Thalidomide, a Non-Specific Inhibitor of TNFalpha 435
6.5 Thalidomide As an Anti-Cancer Agent 436
6.6 Thalidomide and Renal Cell Cancer 436
6.7 TNFa As a Specific Target Anti-TNFalpha Monoclonal Antibodies Infliximab 439
6.8 The Future for TNFalpha-Related Treatment 441
References 442
Chapter 24 451
Molecular Markers for Predicting Prognosis of Renal Cell Carcinoma 451
1 Introduction 451
2 Expression Arrays 452
2.1 Studies of Individual Prognostic Markers for RCC 456
3 Prognostic Molecular Markers 459
3.1 Cell Proliferation/Cell Cycle Regulation 459
3.2 Cell Adhesion 461
3.3 Apoptosis 462
3.4 Degradation of the Extracellular Matrix 462
3.5 Immune Regulation 463
3.6 Hypoxia-Inducible Factors 463
3.7 Multimarker Prognostic Model 464
4 Conclusion 465
References 465
Chapter 25 474
Adjuvant Therapy for Renal Cell Carcinoma: Targeted Approaches 474
1 Introduction 474
2 Determination of the High-Risk Patient 476
3 Adjuvant Local Therapy 478
3.1 Radiation Therapy 478
3.2 Energy Ablation Therapy and Embolization 479
4 Adjuvant Systemic Therapy 479
4.1 Hormone Therapy 479
4.2 Immunological Therapy 480
4.2.1 Cytokine Therapy 480
4.2.2 Adoptive Immunotherapy 482
4.2.3 Tumor Vaccines 482
4.2.4 Monoclonal Antibody Therapy 483
4.3 Chemotherapy 486
4.4 Antiangiogenic Therapy 486
4.5 Small Molecule Kinase Inhibitors 487
5 Conclusion 489
References 490
Index 497