| Preface | 6 |
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| Contents | 8 |
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| Contributors | 10 |
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| 1 Systemic Therapy for Ovarian Cancer, Current Treatment, Recent Advances, and Unmet Needs | 13 |
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| 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 |
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| 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 |
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| 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 |
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| 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 |
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| 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 |
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| 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 Therapeu
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