Emerging Therapeutic Targets in Ovarian Cancer (eBook)

Preface 6
Contents 8
Contributors 10
1 Systemic Therapy for Ovarian Cancer, Current Treatment, Recent Advances, and Unmet Needs 13
1.1 Introduction 13
1.2 Existing Treatments for Newly Diagnosed Ovarian Cancer 14
1.2.1 Early-Stage Ovarian Cancer (I--IIa) 15
1.2.2 Advanced-Stage (IIb--IV) Ovarian Cancer 16
1.3 Existing Treatments for Relapsed Disease 19
1.3.1 Platinum-Sensitive Disease 21
1.3.2 Platinum-Resistant Disease 23
1.3.3 Surgical Resection for Relapsed Ovarian Cancer 24
1.4 Recent Advances 25
1.4.1 Chemotherapy 26
1.4.2 Resistance-Modifying Agents 28
1.4.3 Hormonal Therapy 30
1.4.4 Immunotherapy 30
1.4.5 Molecularly-Targeted Therapies 30
1.4.5.1 Angiogenesis Inhibitors 30
1.4.5.2 Poly(ADP)ribose Polymerase (PARP) Inhibitors 32
1.4.5.3 EGFR and HER2 Inhibitors 32
1.4.5.4 Other Signalling Molecules 33
1.5 Unmet Needs 33
1.5.1 Advanced Ovarian Cancer Remains Incurable 33
1.5.2 The Role of Maintenance Therapy 34
1.5.3 Optimal Time to Commence Treatment for Recurrent Disease 35
1.5.4 Challenges Facing the Optimal Use of Targeted Therapies 35
1.5.5 Global Resources 36
1.6 Conclusion 37
References 37
2 Discovery of Novel Targets 46
2.1 Introduction 46
2.2 The Historic Perspective of Drug Development Empirical Approaches 47
2.3 Genomics 48
2.4 Tumor Histology 49
2.5 Genomic Analysis Reveals Heterogeneity Within Ovarian Tumors Based upon Tumor Grade 50
2.6 Bioinformatic Analysis Reveals Activated Pathways Within LMP and Low-Grade Ovarian Cancer 51
2.7 High-Grade Ovarian Cancer 54
2.8 Future Directions in the Identification of Novel Therapeutic Targets 58
2.9 Conclusion 59
References 60
3 Novel Anti-angiogenic Therapies in Ovarian Cancer 62
3.1 Introduction 62
3.1.1 Angiogenesis as a Therapeutic Target 63
3.1.2 Angiogenesis in Ovarian Cancer 64
3.2 Anti-VEGF Agents 65
3.2.1 Bevacizumab (Avastin) 65
3.2.1.1 Single-Agent Bevacizumab in Patients with Recurrent Ovarian Cancer 65
3.2.1.2 Bevacizumab in Combination with Chemotherapy in Patients with Recurrent Ovarian Cancer 67
3.2.1.3 Bevacizumab in Combination with Carboplatin and Paclitaxel in the First-Line Setting 68
3.2.2 Other Anti-VEGF Agents 69
3.2.2.1 Aflibercept 69
3.2.2.2 Receptor Tyrosine Kinase Inhibitors 70
3.2.2.3 Combination Anti-VEGF and Multi-target Therapy 73
3.2.2.4 Vascular Disrupting Agents 73
3.3 Other Anti-angiogenic Compounds 74
3.4 Safety Profile of Anti-angiogenic Agents 75
3.5 Outlook for Anti-angiogenic Therapy: Future Trials and Tribulations 76
References 79
4 Targeting the AKT Pathway in Ovarian Cancer 84
4.1 Introduction 84
4.2 The PI3K/AKT Pathway 85
4.3 Aberrations in the PI3K/AKT Pathway in Ovarian Cancer 88
4.4 The Role of the PI3K/AKT Pathway in Platinum Resistance in Ovarian Cancer 89
4.5 Targeting the AKT Pathway 90
4.6 AKT Inhibitors 91
4.6.1 ATP-Competitive Inhibitors 91
4.6.1.1 GSK690693 91
4.6.1.2 Abbot Compound A-443654 94
4.6.2 Allosteric Inhibitors 94
4.6.2.1 MK-2206 94
4.6.2.2 AKT/Protein Kinase B Signalling Inhibitor-2 (API-2) 95
4.6.2.3 AKTi-1, AKTi-2, AKTi-1,2 96
4.6.3 Peptide-Based Inhibitors 96
4.6.3.1 AKT-in 96
4.6.4 Lipid-Based Inhibitors 97
4.6.4.1 Phosphatidylinositol Ether Lipid Analogues (PIAs) 97
4.6.4.2 Alkylphospholipids (APLs) 97
4.6.4.3 Perifosine 97
4.7 PI3K and mTOR Inhibition 98
4.7.1 PI3K Inhibitors 98
4.7.2 mTOR Inhibitors 99
4.8 Conclusions and Future Directions 100
References 101
5 Inhibition of the Src Oncogene: Therapeutic Potential in Ovarian Carcinoma 106
5.1 Introduction 106
5.2 Role of Src in Angiogenesis and Vascular Permeability 108
5.3 Regulation of Tumor Progression Through Cell Adhesion, Spread, and Motility by Src 110
5.4 Src and Chemoresistance 111
5.5 Current Clinical Trials Using Src Inhibitors 112
5.6 Summary 114
References 115
6 Tumour-Specific Synthetic Lethality: Targeting BRCA Dysfunction in Ovarian Cancer 119
6.1 Introduction 119
6.2 An Overview of DNA Damage and Repair 120
6.3 The Roles of BRCA1 and BRCA2 Genes in DNA DSB Repair 121
6.4 Poly(ADP) Ribose Polymerase and SSB Repair/BER 123
6.5 The Concept of Synthetic Lethality as a Cancer Therapeutic Strategy 124
6.6 Preclinical Proof of Concept for PARP Inhibition in Targeting BRCA1 and BRCA2- Associated Cancers 124
6.7 BRCA1 and BRCA2 and Familial Ovarian Cancer 126
6.8 BRCAness as a Wider Therapeutic Target for PARP Inhibitor Therapy 126
6.9 The Development of Companion Diagnostics for BRCAness in Sporadic Tumours 128
6.10 Clinical Development of PARP Inhibitors 128
6.11 Combination PARP Inhibitor Clinical Trials 132
6.12 Single-Agent PARP Inhibitor Clinical Trials 133
6.13 Potential Mechanism-Based Resistance to PARP Inhibitors in BRCA Mutation Carriers 136
6.14 The Clinical Trials Landscape in 2010 in Familial and Sporadic Ovarian Cancers 137
6.15 Conclusions 138
References 138
7 Targeting Inflammatory Pathways in Epithelial Ovarian Cancer 143
7.1 Introduction 143
7.2 Ovarian Cancer-Related Inflammation 145
7.3 Cyclooxygenases and Ovarian Cancer 147
7.4 Cytokines and Chemokines in Ovarian Cancer 148
7.4.1 TNF- 148
7.4.2 IL-6 152
7.4.3 IL-1ß 155
7.4.4 Chemokines and Chemokine Receptors 156
7.4.5 Macrophage Colony-Stimulating Factor (MCSF-1) 158
7.4.6 Macrophage Migration Inhibitory Factor (MIF) 159
7.4.7 Integrins 160
7.5 Clinical Trials with Targeting Ovarian Cancer-Related Inflammation 161
7.5.1 Targeting TNF/TNFR and Downstream Signalling 161
7.5.2 Anti-IL-6 Therapy 162
7.6 Future Directions 163
References 163
8 Epithelial-to-Mesenchymal Transition and Cellular Membrane Receptors in Ovarian Cancer: Moving Forward in the Era of Molecularly Targeted Therapy 175
8.1 Introduction 175
8.2 Epithelial-to-Mesenchymal Transition 176
8.3 EGFR/HER 177
8.4 Insulin-Like Growth Factor Receptor (IGFR) 183
8.5 Integrins 185
8.6 Targeting c-Met 187
8.7 Hedgehog Signaling 189
8.8 Conclusion 190
References 190
9 Epigenetic Therapies 198
9.1 Introduction 198
9.2 Mechanisms of Epigenetic Deregulation 199
9.3 Aberrant DNA Methylation as a Target in Ovarian Cancer 201
9.3.1 Compounds Mediating DNA Demethylation 202
9.3.2 Use of DNMT Inhibitors in Solid Tumours 203
9.4 Histone Acetylation and HDAC Inhibitors 205
9.4.1 HDAC Inhibitors as Single Agent 206
9.4.2 Combined HDAC and Chemotherapeutic Treatments 207
9.5 Improved Targeting of Epigenetic Therapies 207
9.6 Conclusions 208
References 209
10 Ovarian Cancer Immunology and Immunotherapy 212
10.1 Introduction 212
10.2 The Immune Environment in Ovarian Cancer 213
10.2.1 Cells Involved in Ovarian Cancer Immunosuppression 214
10.2.1.1 Regulatory T-Cells 214
10.2.1.2 Dendritic Cells 214
10.2.1.3 Tumour Cells 215
10.2.2 Immunomodulatory Molecules 216
10.2.3 Cytokines 217
10.3 Immunotherapeutic Strategies in Ovarian Cancer 218
10.3.1 Antibodies 219
10.3.2 Peptide Vaccines 221
10.3.3 Cellular Therapies 222
10.3.3.1 Dendritic Cell (DC) Therapy 222
10.3.3.2 Adoptive T-Cell Therapy 222
10.3.4 Other Strategies 223
10.4 Immune Responses After Chemotherapy for Ovarian Cancer 223
10.5 Conclusion 224
References 225
11 Ovarian Cancer Progenitor/Stem Cells: Therapeutic Potential 231
11.1 Introduction Cancer Stem Cells/Progenitor Cells 231
11.1.1 Historical Perspective 231
11.1.2 Terminology 232
11.1.3 Theoretical Importance of Cancer Stem Cells to Treatment, Outcomes, and Recurrent Disease 232
11.2 Identifying Ovarian Cancer Stem Cells and the Cells of Origin 233
11.2.1 Ovarian Cancer Stem Cells 233
11.2.2 Ovarian Cancer Cells of Origin 235
11.3 Therapeutic Potential 239
11.3.1 Therapeutic Targeting of Ovarian Cancer Stem Cells Based on Unique Features 239
11.3.1.1 Cell Surface Markers 240
11.3.1.2 Gene Expression Profiles and Networks 241
11.3.1.3 Growth Characteristics 242
11.3.1.4 Niche 243
11.3.1.5 Epigenetic Features 244
11.4 Critical Questions to Be Addressed 246
11.5 Conclusions 247
References 247
12 Potential for -Folate Receptor-Targeted Treatment for Ovarian Cancer 253
12.1 Biology of Folate Receptors 253
12.1.1 Folate Receptor Isoforms and Distribution in Normal Tissues 254
12.1.2 Folate Receptors and Cancer 254
12.2 Targeting the -FR for Cancer Treatment 257
12.2.1 Selecting Patients for FR-Targeted Therapies 257
12.2.2 Immunotherapies Directed Towards the -FR 257
12.2.3 Small Molecule Therapies Directed to the -FR 259
12.2.3.1 Antifolates 259
12.2.3.2 Therapeutic Agents Conjugated to Folate 261
12.2.3.3 Drug Carriers Conjugated to Folate 262
12.3 Summary and Future Directions 262
References 263
13 New Insights into Tubulin Binders 267
13.1 Microtubules Are the Pharmacodynamic Target of Taxanes 267
13.1.1 Taxane Resistance and Tubulin Function 268
13.1.2 Mutations in -Tubulin 269
13.1.3 Mutations in TP53 and Taxane Response 270
13.1.4 Misexpression of Tubulin Subtypes 270
13.1.5 Microtubule Stability as a Mechanism of Resistance 271
13.2 Microtubules and the Cell Cycle 273
13.2.1 Mechanistic Insights into Taxane Response 274
13.3 Novel Pathways and Biomarkers for Taxane Response 275
13.3.1 Chromosomal Instability May Predict Taxane Response 275
13.4 Novel Tubulin-Binding Drugs 276
13.4.1 The Epothilones 276
13.4.1.1 Patupilone 277
13.4.1.2 Ixabepilone 277
13.4.1.3 Sagopilone 278
13.4.1.4 Epothilone D Compounds 278
13.4.2 Tubulin-Binding Agents from Marine Organisms 278
13.5 Alternative Strategies for Paclitaxel Administration 279
13.6 Conclusions 280
References 280
Index 287