Targeted Therapies in Cancer: (eBook)

Introduction 6
Contents 8
Causality in Medicine 10
The Evolution of the Biomedical Paradigm in Oncology: Implications for Cancer Therapy 14
2.1 Introduction 14
2.2 The Epistemological Evolution of Scientific Medicine 15
2.3 From Magic Bullets to Targeted Therapies: Many Treatments but the Same Philosophy 16
2.4 The Darwinian paradigm in oncology 18
2.5 The Origins of Oncological Darwinism 19
2.6 From Speculations to Reality and Beyond: Some Implications of a Darwinian View of Cancer Progression 23
2.7 Epilogue 25
References 25
Anticancer Drug Discovery and Development 28
3.1 Introduction 28
3.2 The Evolution of Cancer Drug Discovery 29
3.3 Target-Driven Drug Discovery 30
3.4 R& D Pipeline in NMS
3.5 Conclusions 48
References 49
Beyond VEGF: Targeting Tumor Growth and Angiogenesis via Alternative Mechanisms 52
4.1 Introduction 52
4.2 Checkpoint 1 (Chk1) 53
4.3 Results and Discussion 53
4.4 c-Met 57
4.5 Results and Discussion 57
References 61
Aurora Kinases and Their Inhibitors: More Than One Target and One Drug 63
5.1 The History of Aurora Kinases 63
5.2 Aurora Kinases: Functions in Different Steps in Mitosis 64
5.3 Advanced Small Molecule Aurora Kinase Inhibitors 68
5.4 A Case History: PHA-739358 71
5.5 Conclusion 77
References 78
Signalling Pathways and Adhesion Molecules as Targets for Antiangiogenesis Therapy in Tumors 83
6.1 Introduction 83
6.2 Pathways in Angiogenesis and Lymphangiogenesis 84
6.3 Cell-matrix Adhesion in Angiogenesis: Endothelial Integrins 88
6.4 Cell-cell Adhesion in Angiogenesis: Endothelial Cadherins 91
6.5 Conclusions 92
References 93
Developing T-Cell Therapies for Cancer in an Academic Setting 97
7.1 Introduction 97
7.2 Epstein - Barr Virus 98
7.3 Treatment of Type 3 Latency Tumors ( Immunoblastic Lymphoma) 99
7.4 Use of EBV CTLs to Treat Malignancy in the Immuno- competent Host 99
7.5 Increasing the Frequency of Tumor Reactive T-Cells 101
7.6 Targeting Tumor Stem Cells 101
7.7 CD40L/IL2 B-CLL Tumor Vaccines 103
7.8 Targeting Side Population Tumor Cells with Tumor Vaccines 103
7.9 How Does Immunization with Mature Tumor Cells Induce an Antitumor- Stem- Cell Response? 105
7.10 Implementation of T-Cell Therapeutics in an Academic Environment 106
7.11 Summary 107
References 107
Anticancer Cell Therapy with TRAIL-Armed CD34+ Progenitor Cells 109
8.1 Introduction 109
8.2 Adenoviral Transduction of CD34+ Cells 112
8.3 In Vitro Activity of CD34-TRAIL+ Cells 112
8.4 In Vivo Antitumor Activity of CD34-TRAIL+ Cells 113
8.5 Toxicity of CD34-TRAIL+ Cells 114
8.6 Histologic Analysis 114
8.7 Conclusions 116
References 117
Linking Inflammation Reactions to Cancer: Novel Targets for Therapeutic Strategies 121
9.1 Introduction 121
9.2 Macrophage Polarization 122
9.3 Macrophage Recruitment at the Tumor Site 123
9.4 TAMs Express Selected M2 Protumoral Functions 125
9.5 Targeting TAM 127
References 131
Clinical Development of Epidermal Growth Factor Receptor ( EGFR) Tyrosine Kinase Inhibitors: What Lessons Have We Learned? 137
10.1 Introduction 137
10.2 The HER Family of Receptors 137
10.3 Early Days Rationale to Target the EGFR 138
10.4 Strategies to Inhibit the EGFR 139
10.5 Gefitinib 139
10.6 Erlotinib 140
10.7 Insights Gained in the Role of EGFR in Cancer 141
10.8 Lessons Learned 146
References 148
GIST As the Model of Paradigm Shift Towards Targeted Therapy of Solid Tumors: Update and Perspective on Trial Design 153
11.1 Introduction 153
11.2 The Introduction of Inhibitors of KIT 154
11.3 Randomized Phase III Studies of Imatinib in GIST 155
11.4 The Possible Relevance of Genotyping 156
11.5 The Consequences for Trial Design 159
11.6 The Importance of Continuing Drug Administration 160
11.7 Second Line Treatment in Metastatic Disease 160
11.8 Conclusion 161
References 162
Monoclonal Antibodies in the Treatment of Malignant Lymphomas 164
12.1 Introduction 164
12.2 Mechanisms of Action of Monoclonal Antibodies 164
12.3 Mechanisms of Resistance 166
12.4 Safety and Tolerability 167
12.5 Clinical Studies 168
12.6 Rituximab in follicular lymphoma 168
12.7 RIT in Follicular Lymphoma 172
12.8 Other Monoclonal Antibodies 173
12.9 Rituximab in Diffuse Large B-cell Lymphoma 174
12.10 Monoclonal Antibodies in Other Lymphomas 175
12.11 MAb and High Dose Therapy (HDT) with Autologous Stem Cell Transplantation ( ASCT) 177
12.12 Conclusion 178
References 178
Molecular Network Analysis using Reverse Phase Protein Microarrays for Patient Tailored Therapy 186
13.1 Introduction 186
13.2 Molecular Heterogeneity and the Promise of Proteomics 187
13.3 Protein Microarrays for Molecular Analysis 188
13.4 Design of Reverse Phase Protein Microarrays for Clinical Use 190
13.5 Signal Pathway Profiling of Human Cancer Using RPMA 192
13.6 A Vision for Patient Tailored Therapy Using Proteomics 193
References 194
Index 196