Targeted Cancer Therapy (eBook)

Dedication 6
Preface 7
Contents 8
Contributors 10
Perspectives: Bench to Bedside and Back 12
Abstract 12
1. INTRODUCTION 13
2. DEVELOPMENT OF ONE OF THE FIRST TARGETED THERAPIES: ALL- TRANS RETINOIC ACID AND THE BEDSIDE TO BENCH PARADIGM 14
3. A MODEL OF BENCH TO BEDSIDE TARGETED DRUG DEVELOPMENT: THE STORY OF IMATINIB IN PHILADELPHIA- POSITIVE ACUTE LYMPHOBLASTIC LEUKEMIA, CHRONIC MYELOGENOUS LEUKEMIA, AND GASTROINTESTINAL STROMAL TUMORS 16
3.1. Imatinib as a Model for Discovery of Approaches to Overcome Resistance 17
3.2. Mathematical Modeling as a Tool for Discovery 18
3.3. GIST and the Development of Targeted Therapy 19
4. WHAT IS OLD IS NEW AGAIN: DECITABINE AND THE DAWN OF EPIGENETICS 21
5. NEW MODEL OF CARCINOGENESIS: CANCER STEM CELL HYPOTHESIS 24
6. LOOKING FORWARD: THE FUTURE OF TRANSLATIONAL MEDICINE 26
REFERENCES 26
Targeted Therapy in Acute Myelogenous Leukemia 31
CONTENTS 31
Abstract 31
1. INTRODUCTION 31
2. ATRA AND ATO IN APL 32
3. AGENTS TARGETING CD33 35
3.1. Lintuzumab 35
3.2. Gemtuzumab Ozogamycin (Mylotarg) 35
4. IODINE-131 ANTI-CD45 ANTIBODY 38
5. FLT3 INHIBITORS 38
6. FARNESYL TRANSFERASE INHIBITORS 39
7. EPIGENETIC THERAPY 40
7.1. Hypomethylating Agents (Azacitidine and Decitabine) 40
7.2. Hypomethylating Agents + Histone Deacetylase Inhibitors 44
7.3. Epigenetic-Acting Drugs as Sensitizers to Other Therapies 44
7.4. Antagonists of BCL-2 and MDR1 45
7.5. Aurora Kinase Inhibitors 45
7.6. Immune System Modulators 45
8. GENERAL ISSUES 47
8.1. Which Patients Are Candidates for Targeted Therapies? 47
8.2. New Response Criteria 48
8.3. Clinical Trial Design 48
REFERENCES 49
Targeted Therapy in Breast Cancer 53
CONTENTS 53
Abstract 53
1. INTRODUCTION 53
2. MOLECULAR MECHANISMS INVOLVED FOR BREAST CANCER GROWTH AND PATIENT SURVIVAL 55
2.1. Hormone Receptors 55
2.2. Receptor Tyrosine Kinases 55
2.3. Key Signaling Pathways for Breast Cancer 57
3. TARGETED THERAPIES FOR THE TREATMENT OF BREAST CANCER 58
3.1. Modulation of Estrogen Receptor Signaling 58
3.2. Targeting the HER Signaling Pathway 59
3.3. Targeting VEGF for the Treatment of Breast Cancer 63
3.4. Other Targeted Drugs for Breast Cancer Therapy 64
4. FUTURE DIRECTION OF TARGETED THERAPY FOR BREAST CANCER 64
REFERENCES 65
Targeted Therapy in Chronic Lymphocytic Leukemia 70
CONTENTS 70
Abstract 70
1. INTRODUCTION 71
1.1. Current Therapies 71
1.2. Prognosis 76
2. MOLECULAR MECHANISMS PERTINENT TO DISEASE 77
3. TARGETED THERAPIES 77
3.1. Alemtuzumab 77
3.2. Rituximab 78
3.3. Alemtuzumab and Rituximab 83
3.4. Ofatumumab 83
3.5. Lenalidomide 83
3.6. Vaccines and Gene Therapy 87
3.7. Lumiliximab 87
3.8. Flavopiridol 88
3.9. Talabostat 88
3.10. Oblimersen 88
3.11. Gossypol 89
3.12. Obatoclax 89
3.13. Heat Shock Protein 90 Inhibitors 89
3.14. Targeted Therapies in Advanced Experimental Trials 89
4. FUTURE DIRECTIONS IN MOLECULAR THERAPEUTICS 90
REFERENCES 91
Targeted Therapy in Chronic Myeloid Leukemia 96
CONTENTS 96
Abstract 96
1. INTRODUCTION 97
2. IMATINIB: FRONTLINE THERAPY FOR CML 98
2.1. Survival Advantage 98
2.2. Long-Term Safety 99
2.3. Imatinib Dose Schedules 99
2.4. Monitoring Response to Imatinib Therapy and Minimal Residual Disease 100
2.5. Imatinib Resistance 100
2.6. Overcoming Imatinib Resistance 101
3. DASATINIB 101
3.1. Optimizing Dose and Schedule 102
3.2. Frontline Therapy 102
4. NILOTINIB 103
4.1. Frontline Therapy 103
5. BOSUTINIB (SKI606) 104
6. INNO-406 104
7. OTHER AGENTS 104
8. IMMUNOTHERAPY AND RESIDUAL DISEASE 104
9. CONCLUSION AND FUTURE PERSPECTIVES 105
REFERENCES 105
Targeted Therapy in Colorectal Cancer 109
CONTENTS 109
Abstract 109
1. INTRODUCTION 109
1.1. Overview of Treatment 110
1.2. Familial Predispositions 111
2. MOLECULAR MECHANISMS 112
2.1. Tumorigenesis Pathways 112
2.2. Cytokine Mechanisms 115
3. MOLECULAR TARGETED THERAPIES 116
3.1. VEGF 117
3.2. EGFR 119
3.3. Combination of VEGF and EGFR 121
3.4. Other Agents in Late Development 122
4. FUTURE DIRECTIONS OF MOLECULAR THERAPEUTICS 123
4.1. Moving Beyond EGFR and VEGF 123
4.2. Efficient Trial Design 124
4.3. Translating Our Understanding of Colorectal Biology to the Clinical Setting 124
4.4. Conclusions 125
5. REFERENCES 125
Targeted Therapy in Non-Small Cell Lung Cancer 132
CONTENTS 132
Summary 132
1. INTRODUCTION 132
2. PUTATIVE TARGETS AND AGENTS IN NSCLC: ErbB FAMILY MEMBERS 133
2.1. Epidermal Growth Factor Receptor 133
2.2. Anti-erbB2 Antibodies 147
3. PUTATIVE TARGETS AND AGENTS IN NSCLC: VASCULAR ENDOTHELIAL GROWTH FACTOR AND ITS RECEPTOR 147
3.1. Bevacizumab 147
3.2. VEGF Trap (AVE0005) 148
3.3. ZD6474 (Vandetanib) 148
3.4. Sorafenib (BAY 43-9006) 149
3.5. Sunitinib 149
3.6. Axitanib (AG-013736) 149
3.7. Nitroglycerin 149
4. NSCLC AND OTHER ANTIANGIOGENIC AGENTS 149
4.1. CXCL8 (Interleukin-8) and CXCR2 Antagonists 149
4.2. Matrix Metalloproteinase Inhibitors 150
4.3. Interferons 150
5. OTHER INHIBITORS TO GROWTH IN NSCLCs 151
5.1. Src Inhibitors 151
5.2. KRAS Inhibitors 151
5.3. Insulin-like Growth Factor and Its Receptor and the Receptor Inhibitors 151
5.4. mTOR Inhibitors 152
5.5. Protein Kinase C Inhibitors 152
5.6. Proteosome Inhibitors 153
5.7. Retinoid X Receptor Targeting 153
5.8. Cyclooxygenase-2 Inhibitors 153
5.9. SGN-15 154
6. CONCLUSION 154
REFERENCES 154
Targeted Therapy in Lymphoma 164
CONTENTS 164
Abstract 164
1. INTRODUCTION 164
2. TARGETING SURFACE ANTIGENS 165
2.1. CD20 165
2.2. CD22 166
2.3. CD19 167
2.4. CD40 168
2.5. CD30 168
2.6. CD80 169
2.7. CD2 170
2.8. CD52 170
2.9. Interleukin-13 170
3. TARGETING SURFACE RECEPTORS 170
3.1. Anti-TRAIL Death Receptors 170
3.2. BAFF and its Receptors 171
3.3. RANK Ligand (RANKL) and its Receptors 172
4. TARGETING LYMPHOMA CELLS WITH SMALL MOLECULES 172
4.1. Proteasome Inhibitors 172
4.2. mTOR Inhibitors 173
4.3. Heat Shock Protein Inhibitors 175
4.4. Histone Deacetylases Inhibitors 176
4.5. Bcl-2 178
4.6. BCL6 179
4.7. Mitotic Kinases 179
4.8. Protein Kinase (CPKC)- 181
4.9. Extracellular Signal-Regulated Kinase 181
5. TARGETING TUMOR ANGIOGENESIS 181
5.1. Targeting VEGF and its Receptors 181
REFERENCES 182
Targeted Therapy in Melanoma 190
CONTENTS 190
Summary 190
1. INTRODUCTION 191
2. SIGNALING PATHWAYS 192
2.1. RAS/RAF/MAPK Pathway 192
2.2. PI3K/AKT/mTOR Pathway 195
2.3. NF B 197
3. RECEPTOR TYROSINE KINASE INHIBITORS 198
4. PROAPOTOTIC PATHWAYS 199
4.1. Bcl-2 199
5. POLY(ADP-RIBOSE) POLYMERASE INHIBITORS 201
6. ANTIANGIOGENESIS STRATEGIES 201
6.1. VEGF Targeting 202
6.2. Thalidomide and Immunomodulatory Drugs 202
6.3. Anti-integrins 204
7. ANTI-CTLA-4 ANTIBODY 205
8. FUTURE DIRECTIONS 209
REFERENCES 210
Targeted Therapy in Multiple Myeloma 219
CONTENTS 219
Abstract 219
1. INTRODUCTION 220
2. MOLECULAR PATHOGENESIS OF MULTIPLE MYELOMA 220
3. ROLE OF THE MYELOMA CELL AND ITS MICROENVIRONMENT 223
3.1. Multiple Myeloma Cells and Adhesion Molecules 223
3.2. Cytokines 224
3.3. Signaling Cascades in the Development of Multiple Myeloma 225
4. THERAPIES TARGETING MM CELLS IN THE BONE MARROW MICROENVIRONMENT 226
4.1. Thalidomide and its IMiD Analogues 226
4.2. Thalidomide Maintenance Therapy 228
4.3. Other Lenalidomide-Based Combination Regimens 228
4.4. Proteasome Inhibitors and NF 229
4.4. Proteasome Inhibitors and NF B as a Therapeutic Target: Bortezomib (PS-341, Velcade) 229
4.5. Arsenic Trioxide 232
5. OTHER TARGETED AGENTS IN EARLY DVELOPMENT 233
5.1. RAS as a Therapeutic Target and Farnesylation Inhibitors 233
5.2. Bcl-2 as a Therapeutic Target 234
5.3. Heat Shock Protein-90 as a Therapeutic Target: KOS-953 235
5.4. Histone Deacetylase as a Therapeutic Target: SAHA 235
6. CONCLUSION AND FUTURE 236
REFERENCES 236
Targeted Therapy in Myelodysplastic Syndrome 243
CONTENTS 243
Abstract 243
1. BACKGROUND 244
2. MOLECULAR PATHOGENESIS OF MDS 246
3. TARGETED AGENTS FOR THE TREATMENT OF MDS 247
3.1. Epigenetic Therapy 247
3.2. Antiangiogenesis Inhibitors 254
3.3. Signal Transduction Inhibitors 258
3.4. Targeting EVI1 Overexpression 260
3.5. Vaccination Approaches for MDS 260
4. FUTURE DIRECTION OF MOLECULAR THERAPEUTICS IN MDS 261
REFERENCES 262
Targeted Therapy in Epithelial Ovarian Cancer 267
CONTENTS 267
Abstract 267
1. EPIDEMIOLOGY AND NATURAL HISTORY OF OVARIAN CANCER 267
2. MANAGEMENT OF ADVANCED OVARIAN CANCER 268
3. UNIQUE ASPECTS OF OVARIAN CANCER PERMITTING STUDY OF NOVEL MANAGEMENT STRATEGIES 269
4. POTENTIAL FOR “TARGETED THERAPY” OF OVARIAN CANCER 270
5. EXPERIENCE WITH “TARGETED THERAPY” OF OVARIAN CANCER 271
5.1. HER2 Overexpression 271
5.2. Epidermal Growth Factor Receptor Overexpression 271
5.3. Tyrosine Kinase Inhibition 271
5.4. Antiangiogenesis Agents 272
6. CONCLUSION 273
REFERENCES 273
Targeted Drug Therapy in Pancreatic Cancer 276
CONTENTS 276
Abstract 276
1. INTRODUCTION 277
2. BIOLOGY OF THE DISEASE 278
3. AGENTS TARGETING EPIDERMAL GROWTH FACTOR RECEPTOR 279
4. AGENTS TARGETING THE KRAS PROTO- ONCOGENE 282
5. AGENTS TARGETING VASCULAR ENDOTHELIAL GROWTH FACTOR 282
6. AGENTS TARGETING MATRIX METALLOPROTEINASES 283
7. AGENTS INHIBITING PHOSPHOINOSITOL-3-KINASE 284
8. AGENTS TARGETING SIGNAL TRANSDUCER AND ACTIVATOR OF TRANSCRIPTION 3 285
9. AGENTS TARGETING TRANSCRIPTION FACTOR NUCLEAR FACTOR- B 286
10. AGENTS TARGETING BCL-2/ADENOVIRUS E1B 19-KDA PROTEIN- INTERACTING PROTEIN 287
11. PATIENT SELECTION AND TRIAL DESIGN FOR STUDIES WITH TARGETED AGENTS 287
11.1. Patient Population Heterogeneity 287
11.2. Appropriate Endpoints to Assess Drug Activity 288
11.3. Changes in Trial Design 288
12. CONCLUSION 288
REFERENCES 289
Targeted Therapy in Prostate Cancer 293
CONTENTS 293
Abstract 293
1. INTRODUCTION 293
2. TARGETING THE ANDROGEN RECEPTOR 294
2.1. Reducing Circulating Androgen Concentrations 294
2.2. Modulating Protein Levels and Activation of the AR 296
2.3. Targeting Nongenomic Mechanisms of AR Activation by Signaling Cross- Talk 296
3. TARGETING ANTIAPOPTOTIC PROTEINS 298
4. TARGETING PATHWAYS RELATED TO ANGIOGENESIS 299
5. TARGETING PATHWAYS IN BONE METASTASIS 300
6. HARNESSING IMMUNOTHERAPEUTIC AGENTS 301
6.1. Modifying T-Cell Co-stimulatory Pathways 301
6.2. Boosting Host Antigen Presentation 302
7. CONCLUSION 303
REFERENCES 303
Targeted Therapy in Renal Cell Carcinoma 309
CONTENTS 309
Abstract 309
1. EPIDEMIOLOGY 309
2. PATHOLOGY AND GENETICS 310
3. MOLECULAR BIOLOGY 310
4. TARGETING AGENTS FOR RENAL CELL CARCINOMA 312
4.1. Bevacizumab (Avastin) 312
4.2. Sorafenib (Bay 43-9006) 313
4.3. Sunitinib (Sutent) 313
4.4. Axitinib (AG-013736) 314
4.5. Temsirolimus (CCI-779) 314
4.6. Epidermal Growth Factor Blocking Agents 314
5. SUMMARY AND FUTURE DIRECTIONS 316
5.1. Pharmacokinetics and Pharmacodynamics 316
5.2. Necessity Versus Sufficiency of Pathway Inhibition 316
5.3. Inherent or Acquired Resistance to Therapy 317
REFERENCES 317
Targeted Therapy of Sarcoma 321
CONTENTS 321
Abstract 321
1. INTRODUCTION 321
1.1. Overview of Soft Tissue Sarcomas and Bone Tumors 321
1.2. Molecular Alterations in Soft Tissue Sarcomas and Bone Tumors 322
2. TARGETED THERAPIES 325
2.1. Targeting Growth Factor Pathways 325
2.2. KIT Receptor Tyrosine Kinase in Gastrointestinal Stromal Tumors 326
2.3. Platelet-Derived Growth Factor in Dermatofibrosarcoma Protuberans 328
2.4. ALK Kinase in Inflammatory Myofibroblastic Tumors 330
2.5. Desmoid Tumor–ER Inhibition 331
2.6. Inducing Apoptosis 332
2.7. Apo2 Ligand/TRAIL and Bone Tumors 332
2.8. Rhabdomyosarcoma and Potential Therapeutic Targets 334
3. CONCLUSIONS 335
REFERENCES 335
Targeted and Functional Imaging 339
CONTENTS 339
Abstract 339
1. INTRODUCTION 340
2. CLINICAL USE OF FUNCTIONAL IMAGING 340
3. IMAGING IN CLINICAL TRIALS 341
4. IMAGING AGENTS 342
5. MEASURING TARGET DIRECTLY VERSUS DOWNSTREAM EFFECTS 342
6. NUCLEAR MEDICINE IMAGING 346
6.1. Radiopharmaceuticals 346
6.2. Physics 346
6.3. PET Physics Introduction 346
7. MAGNETIC RESONANCE 352
7.1. Physics 352
8. DCE-MRI 355
8.1. DCE-MR Physics 356
8.2. Clinical Trials Using DCE-MRI 357
9. MR SPECTROSCOPY 359
9.1. Physics 359
9.2. Clinical Trials Using MR Spectroscopy 360
10. BIOPSY 362
11. FUTURE OF TARGETED IMAGING 362
REFERENCES 363
Combining Targeted Therapies 365
CONTENTS 365
Abstract 365
1. INTRODUCTION 366
2. WHY COMBINE ANTICANCER AGENTS AND SPECIFICALLY TARGETED THERAPIES? 366
3. TARGETED AGENTS IN COMBINATION WITH CYTOTOXIC CHEMOTHERAPEUTIC AGENTS 367
3.1. Experience With Trastuzumab 367
3.2. Lessons from the Use of EGFR Tyrosine Kinase Inhibitors as Targeted Agents 368
3.3. Importance of Timing When Combining Targeted Therapy and Cytotoxic Chemotherapy 369
4. COMBINATIONS OF MOLECULARLY TARGETED ANTICANCER AGENTS 370
4.1. Underlying Mechanisms of Tumorigenesis and Combination Therapies: Pertinent Considerations 370
4.2. Lessons Learned from Sorafenib and its Combinations 372
4.3. Signaling Pathways and Cross Talk in Combination Therapies 372
4.4. Variables to Consider When Designing Effective Combinations of Targeted Agents 377
4.5. Multitargeted Agents and Combination Treatment Design 377
5. IMPROVING PRECLINICAL MODELS 378
6. MOVING TOWARD PERSONALIZED COMBINATIONS 378
7. BARRIERS TO COMBINATORIAL TARGETED THERAPY IN CANCER TREATMENT 381
REFERENCES 383
Drug Development in Cancer Medicine: Challenges for Targeted Approaches 386
CONTENTS 386
Abstract 386
1. INTRODUCTION 387
2. SELECTION OF TARGETS FOR CANCER THERAPEUTICS 388
2.1. Signal Transduction Pathways 388
2.2. Cellular Differentiation 388
2.3. Cellular Migration/Invasion 393
2.4. Cellular Survival/Programmed Cell Death 395
2.5. Angiogenesis 395
2.6. Immune Modulation 396
3. CHALLENGES ASSOCIATED WITH TARGETED ANTICANCER AGENTS 396
3.1. Drug-Related Challenges 396
3.2. Target-Related Challenges 398
3.3. Tumor-Related Challenges 400
4. DRUG DEVELOPMENT PROCESS 401
4.1. Clinical Development and Marketing Approval 401
4.2. Study Endpoints 402
5. CONSIDERATIONS OF POTENTIAL FUTURE APPROACHES 403
5.1. Imatinib Mesylate: Outlier or Precursor of a New Era of Successful Therapies in Cancer Medicine? 403
5.2. Targeted Therapies Against Solid Malignancies: As Successful as Those Directed Against Their Hematologic Counterparts? 405
5.3. Combined Therapies 405
5.4. Tumor Tissue Banking 406
5.5. Prompt Access to Investigational Compounds 407
6. CONCLUSIONS 407
REFERENCES 408
Toward Personalized Therapy for Cancer 414
CONTENTS 414
Abstract 414
1. INTRODUCTION 414
2. WHY IS PERSONALIZED MEDICINE IMPORTANT IN CANCER? 415
3. TO WHAT EXTENT IS CANCER MEDICINE ALREADY PERSONALIZED? 415
4. FUTURE OF PERSONALIZED MEDICINE IN CANCER 419
5. CHALLENGES FOR ACHIEVING PERSONALIZED MEDICINE 422
6. CONCLUSION 425
REFERENCES 425
Index 429