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Principles of Molecular Oncology
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Principles of Molecular Oncology
von: Miguel H. Bronchud, MaryAnn Foote, Giuseppe Giaccone, Olufunmilayo I. Olopade, Paul Workman
Humana Press, 2008
ISBN: 9781597454704
420 Seiten, Download: 8521 KB
 
Format:  PDF
geeignet für: Apple iPad, Android Tablet PC's Online-Lesen PC, MAC, Laptop

Typ: B (paralleler Zugriff)

 

 
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Inhaltsverzeichnis

  Foreword 5  
  Preface 12  
  Contents 14  
  Contributors 16  
  Color Plates 18  
  Chapter 1 Selecting the Right Targets for Cancer Therapy 19  
     1.1 Introduction 19  
     1.2 The Evolution of a Cancer 20  
        1.2.1 Relatively Old Views on Carcinogenesis 21  
        1.2.2 More Modern Views on Carcinogenesis 21  
        1.2.3 Cancers are Monoclonal, but the Carcinogenesis Process is Probably Polyclonal 22  
        1.2.4 Towards a Definition of “Matrix of Targets” 26  
     1.3 Cancer can be Prevented by both Primary and Secondary Prevention 30  
     1.4 The Era of Targeted Therapies 33  
        1.4.1 Examples of Oncogene Inhibitors (OI) 35  
        1.4.2 Examples of Tumor Suppressor Activators (TSA) 37  
           1.4.2.1 p53 as an Example 38  
           1.4.2.2 pRb as Another Example 38  
        1.4.3 New Approaches to Targeting Loss-Of-Function Mutations in Tumor Suppressor Genes 40  
     References 41  
  Chapter 2 Clinical Importance of Prognostic Factors Moving from Scientifically Interesting to Clinically Useful 45  
     2.1 Introduction 45  
     2.2 Importance of Tumor Markers: Adjuvant Systemic Therapy of Breast Cancer as a Case Study 46  
     2.3 Prognosis versus Prediction 46  
     2.4 How should Tumor Markers be Selected for Clinical Use? 49  
     2.5 Recommending Therapy: How Much Benefit is needed to Justify Treatment? 49  
     2.6 How Can the Relative Strength of a Prognostic Factor be Determined? 50  
     2.7 How Reliable are the Estimates of Relative Strengths of Tumor Markers? 52  
     2.8 How Can the Relative Strengths of Prognostic and Predictive Factors be Applied Clinically? 54  
     2.9 Are There Solid Tumor Markers that Fulfill the TMUGS Criteria for Routine Clinical Use? 56  
     2.10 Summary 57  
     References 57  
  Chapter 3 Genetic Markers in Sporadic Tumors 60  
     3.1 Introduction 60  
     3.2 Genetic Markers Derived from Cancer-Associated Genes 62  
        3.2.1 TP53 62  
        3.2.2 RAS 63  
        3.2.3 BRAF 65  
        3.2.4 her-2/neu 65  
        3.2.5 EGFR 66  
        3.2.6 RET 67  
        3.2.7 BCL2 67  
        3.2.8 BCL1–PRAD1–CCND1 68  
        3.2.9 APC 69  
        3.2.10 MYC 69  
        3.2.11 BCL6 71  
        3.2.12 9p21 Chromosomal Region 71  
        3.2.13 P16INK4a 71  
        3.2.14 p15INK4b 73  
        3.2.15 p14ARF 73  
        3.2.16 KIT 74  
        3.2.17 FLT3 74  
        3.2.18 PTEN 75  
        3.2.19 AKT 76  
        3.2.20 COX 76  
        3.2.21 Chromosome 18q 76  
     3.3 Genetic Markers Derived from Nonrandom Chromosomal Abnormalities 77  
     3.4 Hematopoietic Tumors: Proto-oncogene Activation 78  
        3.4.1 BCL2 78  
        3.4.2 BCL1 79  
        3.4.3 C-MYC 80  
        3.4.4 BCL6 80  
        3.4.5 PAX5 t(9 14)(p13q32)80  
        3.4.6 TAL1 81  
        3.4.7 BCL10 t(1 14)(p22q32) and t(12)(p22p12)81  
        3.4.8 MALT1 t(14 18)(q32q21)82  
     3.5 Hematopoietic Tumors: Chimeric Proteins 83  
        3.5.1 NPM–ALK 83  
        3.5.2 API2-MALT1 t(11 18)(q21q21)84  
        3.5.3 BCR–ABL t(9 22)(q34q11)84  
        3.5.4 PML–RARA t(15 17)(q22q21)85  
        3.5.5 AML–ETO t(8 21)(q22q22)86  
        3.5.6 Other Translocations 86  
     3.6 Solid Tumors 86  
     3.7 Soft Tissues 87  
        3.7.1 EWS-FLI1 t(11 22)(q24 q12)87  
        3.7.2 EWS-ERG t(21 22)(q22q12)87  
        3.7.3 EWS-ETV1 t(7 22) (p22q12)87  
        3.7.4 EWS-FEV t(2 22) (q33q12)87  
        3.7.5 EWS-E1AF t(17 22) (q12q12)87  
        3.7.6 EWS-ZGS t(1 22)(p36.1q12)88  
        3.7.7 FUS-ERG t(16 21) (p11q22)88  
        3.7.8 EWS-ATF1 t(12 22) (q13q12)88  
        3.7.9 EWS-WT1 t(11 22) (p13q12)88  
        3.7.10 TGF-CHN t( 9 3.7.11 EWS-CHOP t(1222)(q13q12)89  
        3.7.12 FUS-CHOP t(12 16)(q13p11)89  
        3.7.13 FUS-ATF1 t(12 3.7.14 PAX3-FKHR t(213)(q35q14) and PAX7-FKHR t(113)(p36q14)89  
        3.7.15 SYT-SSX t(X 18)(p11.2q11.2)90  
        3.7.16 PDGFB-COL1A1 t(17 22) (q22q13)90  
        3.7.17 ETV6-NTRK3, TEL-TRKC t(12 15) (p13q26)90  
        3.7.18 TPM3-ALK t(2 5) (p23q35)90  
        3.7.19 ASPL-TFE t(X 17) (p11q25)91  
        3.7.20 JAZF1-JJAZ1 t(7 17) (p15q21)91  
        3.7.21 FUS-CREB3L1 t(11 16) (p11p11)91  
     3.8 Epithelial Tissue 92  
        3.8.1 RET PTC1 92  
        3.8.2 RET-PTC2 92  
        3.8.3 RET-PTC3/PTC4 92  
        3.8.4 RET-PTC5-PTC9, RET-PCM1, ELKS-RET, and RFP-RET 92  
        3.8.5 NTRK1 and TRK Oncogenes 92  
        3.8.6 TRK 93  
        3.8.7 TRK-T1 93  
        3.8.8 TRK-T3 93  
        3.8.9 PAX8-PPAR. t(2 3)(q13p25)93  
        3.8.10 MECT1-MAML2 t(11 19)(q21p13)93  
        3.8.11 ALPHA-TFBE t(6 11)(p21q12)93  
        3.8.12 BRD4-NUT t(15 19) (q13p13.1)93  
     3.9 Conclusions 93  
     References 95  
  Chapter 4 Genetic Markers in Breast Tumors with Hereditary Predisposition 102  
     4.1 Introduction 102  
     4.2 Molecular Pathology 102  
     4.3 Genomic Instability 103  
     4.4 Oncogenes 109  
        4.4.1 HER2 109  
        4.4.2 C-MYC 110  
     4.5 Tumor Suppressor Genes 110  
        4.5.1 P53 110  
        4.5.2 E-cadherin/catenin Cell Adhesion Complex 111  
     4.6 Cell Cycle and Apoptotic Proteins 112  
        4.6.1 p16 112  
        4.6.2 p21 112  
        4.6.3 p27 112  
        4.6.4 Cyclin D1 113  
        4.6.5 Cyclin E 113  
        4.6.6 Bcl-2 113  
     4.7 Gene Expression Profiles 114  
     4.8 Basal-like Phenotype 115  
     4.9 Epigenetic Lesions 116  
     4.10 Conclusion 117  
     References 117  
  Chapter 5 Circulating Tumor Markers 123  
     5.1 Introduction 123  
     5.2 Use of Markers for Particular Cancers 124  
        5.2.1 Testicular Cancer 124  
        5.2.2 AFP 124  
        5.2.3 Human Chorionic Gonadotrophin 124  
     5.3 Staging of Testicular Cancer 124  
     5.4 Monitoring of Response in Testicular Cancer 125  
     5.5 Monitoring of Remission in Testicular Cancer 127  
     5.6 Tumor Markers in Prostate Cancer 127  
        5.6.1 PSA in Diagnosis 127  
        5.6.2 PSA and Staging 127  
        5.6.3 PSA as Marker of Response to Treatment 127  
           5.6.3.1 Radical Prostatectomy 127  
           5.6.3.2 PSA After Hormonal Therapy and Chemotherapy 128  
     5.7 Gastrointestinal Tumors 128  
        5.7.1 Carcinoembryonic Antigen 128  
        5.7.2 CA 19.9 128  
        5.7.3 Guidelines 129  
     5.8 Ovarian Cancer and CA125 129  
     5.9 Breast Cancer-Related Markers 129  
     References 130  
  Chapter 6 Antibody-Based Proteomics Analysis of Tumor Cell Signaling Pathways 133  
     6.1 Introduction 133  
     6.2 Genomics versus Proteomics Profiling 133  
     6.3 Conventional Proteomics—Two-Dimensional Gel Electrophoresis 134  
     6.4 Antibodies—The Gold Standard for Proteomics Probes 135  
     6.5 Antibody Microarrays 136  
     6.6 Kinexus Antibody-based Integrated Discovery Platform 137  
     6.7 Kinex™ Antibody Microarray Analysis of EGF-treated A431 Cells 137  
     6.8 Kinetworks™ Multi-immunoblotting Analysis of EGF-Treated A431 Cells 142  
     6.9 Comparison of Antibody Microarray and Immunoblotting Results for EGF-treated A431 Cells 142  
     6.10 Antibody-driven Protein and Phospho-site Discovery 147  
     6.11 Variation of EGF Signaling Pathways in Diverse Cell Types 149  
     6.12 Conclusions 149  
     References 149  
  Chapter 7 Gene Expression Arrays for Pathway Analysis in Cancer Research 151  
     7.1 Hallmarks of Cancer and Cell-Signaling Pathways 151  
        7.1.1 DNA Microarrays for Gene Expression Analysis 151  
        7.1.2 Gene Expression Profiles as Markers for Tumor Classification and Prognosis 152  
        7.1.3 Pathway-Focused Gene Expression Profiling 154  
     7.2 Tools for Pathway-Focused Gene Expression Profiling 154  
        7.2.1 Pathway-focused Arrays for Gene Expression Analysis 155  
           7.2.1.1 Hybridization DNA Microarrays 155  
           7.2.1.2 Real-Time PCR arrays 155  
           7.2.1.3 Experimental Design and Analysis for Pathway-focused Arrays 158  
              7.2.1.3.1 Requirement for Biologic Replicates 158  
              7.2.1.3.2 Choosing an Appropriate Array Methodology 159  
              7.2.1.3.3 Sample Considerations 159  
              7.2.1.3.4 Data Analysis Considerations 159  
     7.3 Application of Specific Expression-Profiling Tools in Cancer Research 160  
        7.3.1 Studies of Individual Pathways using Focused Microarrays 160  
        7.3.2 Multipathway Studies using PathwayFinder Arrays 163  
        7.3.3 Application Examples of Real-time PCR Arrays 166  
     7.4 Concluding Remarks 166  
     References 167  
  Chapter 8 Signaling Pathways in Cancer 169  
     8.1 Introduction 169  
     8.2 Signaling Pathways in Normal Development 169  
        8.2.1 External Signals Reset Interlocking Internal Pathways that Dictate Cell Behavior 169  
        8.2.2 Organization of Signaling Pathways 170  
        8.2.3 Complex Developmental Patterns are Built by Simple Intercellular Interactions 170  
        8.2.4 Signaling Resets Cell State 172  
        8.2.5 A Robust and Versatile Design Principle 172  
        8.2.6 Summary: Signaling Pathways in Normal Development 173  
     8.3 Origin of Cancer Cells 174  
        8.3.1 Cancer Stem Cells 174  
        8.3.2 Acquisition and Fixation of Multiple Mutations in Cancer Cells 175  
        8.3.3 Stem Cell Properties 175  
        8.3.4 Mutations that Increase Stem Cell Numbers 176  
        8.3.5 Can Mutations be fixed in Stem Cells if they Only Benefit Stem Cell Derivatives? 177  
        8.3.6 Non-autonomous Mutational Contributions to Cancer Development 177  
        8.3.7 Signal-induced Changes in Chromatin as Selectable Reversible Traits 177  
        8.3.8 Implications of Cellular Ontogeny of Cancer 178  
     8.4 Targets of Signaling Pathway Mutations that Drive Cancer 178  
        8.4.1 Cell Cycles and the G1/S Transition 179  
        8.4.2 Accelerated G1/S Transition can Trigger Senescence and Apoptosis 180  
        8.4.3 Regulation of Cell Growth 180  
        8.4.4 Terminal Limitations on Cell Proliferation: Cell Death and Senescence 181  
        8.4.5 Cell Interactions that Regulate Proliferation within an Epithelium 181  
        8.4.6 Angiogenesis, Epithelial-Mesenchymal Transitions, and Metastasis 181  
     8.5 Signaling Pathways 182  
        8.5.1 Receptor Tyrosine Kinase Pathways 182  
           8.5.1.1 Ras/ERK Pathway 184  
           8.5.1.2 PI3K Pathway 184  
           8.5.1.3 PI3K Pathway Connections to Translation and Cell Growth 185  
           8.5.1.4 Phospholipase C Pathway 185  
           8.5.1.5 Interactions Between RTK Pathway Branches 186  
           8.5.1.6 Mutational Alteration of Receptor TyrosineKinase Pathways in Cancer 186  
           8.5.1.7 Why do RTK Pathway MutationsCause Cancer? 187  
        8.5.2 Wnt Signaling 188  
           8.5.2.1 Mutational Alteration of Wnt Pathways in Cancer 190  
           8.5.2.2 Do Cancers With Activated Wnt Pathways Result From Actions of the Wnt Pathway on Stem Cells? 190  
        8.5.3 Hedgehog Signaling Pathways 192  
           8.5.3.1 Mutational Alteration of Hh Signaling Pathways in Cancer 194  
        8.5.4 Notch Signaling Pathway 195  
           8.5.4.1 Mutational Alteration of Notch Signaling in Cancer 195  
        8.5.5 TGFß/BMP Family Signaling 195  
           8.5.5.1 Mutational Alteration of TGFb Pathways in Cancer 197  
        8.5.6 JAK/STAT Signaling Pathway 197  
           8.5.6.1 Mutational Activation of JAK/STAT Pathway 198  
     8.6 Summary 198  
     References 199  
  Chapter 9 Estrogen Receptor Pathways and Breast Cancer 205  
     9.1 Introduction 205  
     9.2 Biology of Estrogen Receptors 205  
        9.2.1 Structure of ER-a and ER-ß 206  
        9.2.2 AF-1 Domain 206  
        9.2.3 DNA-Binding Domain 207  
        9.2.4 Hinge Region 208  
        9.2.5 Ligand-Binding Domain 208  
        9.2.6 ER Mutations in Breast Cancer 209  
        9.2.7 Mechanisms of Estrogen and ER Signaling 209  
        9.2.8 Ligand-and-ERE-Dependent Activation of ER 209  
        9.2.9 ERE-Independent Genomic Actions of ER 212  
        9.2.10 Ligand-Independent Genomic Activation of ER 213  
        9.2.11 Membrane-Mediated Nongenomic Action of Estrogen 214  
     9.3 Conclusions and Clinical Applications 215  
     References 216  
  Chapter 10 Cyclin-Dependent Kinases and Their Regulators as Potential Targets for Anticancer Therapeutics 223  
     10.1 Introduction 223  
     10.2 Cyclin-Dependent Kinases: A Historical View 223  
     10.3 Cell Cycle CDK and Their Regulators 224  
        10.3.1 Cell Cycle versus Transcriptional CDK 224  
        10.3.2 Cyclins 226  
        10.3.3 CDK Inhibitors 227  
           10.3.3.1 INK4 Proteins 227  
           10.3.3.2 Cip/Kip Proteins 228  
        10.3.4 An Integrative View to CDK Activity Regulation 229  
     10.4 Control of the Cell Cycle by Cdk 230  
        10.4.1 Entry into the Cell Cycle and DNA Replication 230  
        10.4.2 Chromosome Segregation 231  
     10.5 Alteration of CDK and Their Regulators in Human Cancer 232  
        10.5.1 Cell Cycle CDK in Human Cancer 232  
        10.5.2 Tumor-Associated Alterations in CDK Regulators 232  
           10.5.2.1 Cyclins 232  
           10.5.2.2 CDK Inhibitors 233  
           10.5.2.3 Alterations in Other CDK Regulators 235  
        10.5.3 Genetic Alteration of CDK Substrates: The Retinoblastoma Protein 235  
     10.6 Genetic Analysis of CDK and Their Regulators 235  
        10.6.1 Physiologic Roles of G1/S CDK and Their Regulators 235  
        10.6.2 Genetic Analysis of Mitotic CDK 238  
        10.6.3 Tumor Mouse Models 239  
     10.7 Therapeutic Strategies 240  
        10.7.1 Therapeutic Inhibition of CDK4 and CDK6 241  
        10.7.2 Inhibition of CDK2 241  
        10.7.3 Other CDK: CDK3, CDK7, and the Transcriptional CDK 242  
        10.7.4 Inhibition of CDK1 242  
        10.7.5 Selectivity versus Potency in CDK Inhibition 242  
        10.7.6 Alternatives to Small-Molecular ATP Competitors 243  
        10.7.7 Other Cell-Cycle Targets Involved in CDK Regulation 243  
           10.7.7.1 CDK Inhibitory Kinases 243  
           10.7.7.2 Cell Cycle Phosphatases 244  
     10.8 Concluding Remarks 244  
     References 244  
  Chapter 11 Angiogenesis Switch Pathways 254  
     11.1 Introduction 254  
     11.2 Physiologic and Pathologic Angiogenesis 254  
     11.3 Mechanisms of Tumor Neovascularization 255  
        11.3.1 Tumor Angiogenic Switch 255  
        11.3.2 Endothelial Cells: Key Component in Angiogenesis 256  
        11.3.3 Inducers of Angiogenesis 257  
           11.3.3.1 Vascular Endothelial Growth Factor 257  
           11.3.3.2 Fibroblast Growth Factors 257  
           11.3.3.3 Angiopoietins and Tie-2 Receptors 257  
           11.3.3.4 Ephrin and Eph Receptors 258  
           11.3.3.5 Transforming Growth Factor b 258  
           11.3.3.6 Tumor Necrosis Factor a 258  
              11.3.3.6.1 Platelet-Derived Growth Factor/Thymidine Phosphorylase 258  
              11.3.3.6.2 Transforming Growth Factor a and Epidermal Growth Factor 258  
              11.3.3.6.3 Other Angiogenic Compounds 258  
        11.3.4 Cell Adhesion Molecules and Angiogenesis 259  
           11.3.4.2 Selectins 259  
           11.3.4.3 Immunoglobulins 259  
           11.3.4.4 Cadherins 259  
           11.3.4.5 Integrins 259  
           11.3.4.6 Integrin avb3 259  
        11.3.5 Proteases 260  
        11.3.6 Lymphangiogenesis 260  
        11.3.7 Endogenous Inhibitors of Angiogenesis CEP- 7055 Cephalon 1 Tyrosine kinase 261  
     11.4 Prognostic Value of Angiogenesis 262  
     11.5 Therapeutic Approaches 263  
     11.6 Conclusion 265  
     References 266  
  Chapter 12 Apoptosis Pathways and New Anticancer Agents 272  
     12.1 The Apoptotic Core Machinery 272  
     12.2 Apoptosis and Anticancer Therapy 273  
     12.3 TRAIL 274  
     12.4 The BCL-2 Family 275  
     12.5 Approaches for Targeting BCL-2 and Clinical Studies 275  
     12.6 Targeting the IAP Family 277  
        12.6.1 XIAP 278  
           12.6.1.1 Small Molecules Targeting XIAP Function 278  
           12.6.1.2 Antisense-Mediated Targeting of XIAP Expression 278  
        12.6.2 Survivin 279  
     12.7 Conclusions and Future Perspectives 279  
     References 279  
  Chapter 13 Genomic Instability, DNA Repair Pathways and Cancer 284  
     13.1 The Genetic Basis of Cancer 284  
     13.2 Genomic Damage, Cell Heterogeneity, and Genetic Instability are Characteristic of Tumor Cells 284  
     13.3 Responses to DNA Damage 285  
        13.3.1 DNA Repair Pathways 285  
           13.3.1.1 Base Excision Repair (BER) 285  
           13.3.1.2 Nucleotide-Excision Repair (NER) 286  
           13.3.1.3 Double-Strand Breaks (DSB) Homologous Repair System 286  
           13.3.1.4 Double-Strand Breaks (DSB) Nonhomologous End Joining (NHEJ) Repair System286  
           13.3.1.5 Mismatch Repair (MMR) 286  
           13.3.1.6 Translation Synthesis 287  
           13.3.1.7 Other Types of Repair: Methylguanine- Methyltransferases (MGMT) or O6-Alkylguanine-DNA Alkyltransferase (ATase) 287  
        13.3.2 DNA Damage Sensing and Signaling 287  
     13.4 Aberrations in DNA Repair Pathways and Human Cancer 287  
        13.4.1 High-Penetrance DNA Repair Gene Mutations and Hereditary Cancer Predisposition Syndromes 287  
           13.4.1.1 Base Excision Repair MutY-Associated Polyposis288  
           13.4.1.2 Nucleotide Excision Repair and Translation Synthesis: Xeroderma Pigmentosum (XP) 289  
           13.4.1.3 Double-Strand Break Repair: Hereditary Breast Cancer, Hereditary Pancreatic Cancer, and Other Rare Cancer-Prone Syndromes 289  
           13.4.1.4 Mismatch Repair: Hereditary Nonpolyposis Colorectal Cancer 290  
           13.4.1.5 DNA Damage Sensing 290  
        13.4.2 Low-Penetrance Variants of DNA Repair Genes as Cancer-Susceptibility Alleles 290  
           13.4.2.1 Base Excision Repair 290  
           13.4.2.2 Double-Stranded Break Repair 290  
           13.4.2.3 Mismatch Repair 290  
           13.4.2.4 DNA Damage Sensing 291  
        13.4.3 DNA Repair Biomarkers in the Prediction of Response 291  
           13.4.3.1 Markers of DNA Repair and Cisplatin Sensitivity 291  
           13.4.3.2 MGMT and Gliomas 291  
           13.4.3.3 MSI and Response to 5-FU 291  
     13.5 Conclusions 292  
     References 292  
  Chapter 14 Epigenomics and Cancer 295  
     14.1 Introduction 295  
     14.2 DNA Methylation in Healthy Versus Cancer Cells 296  
        14.2.1 Global Genomic Hypomethylation of Transformed Cells 297  
        14.2.2 Hypermethylation-Associated Silencing of Tumor Suppressor Genes 298  
        14.2.3 Identification of New Hypermethylated Genes 300  
     14.3 “Histone Code” of Cancer Cells 301  
        14.3.1 Reversal of Epigenetic Modifications as a Cancer Therapy. 302  
     14.4 Summary and Perspectives in an Epigenetic World 302  
     References 303  
  Chapter 15 Harnessing the Power of Immunity to Battle Cancer: Much Ado about Nothing or All’s Well That Ends Well? 306  
     15.1 Introduction 306  
     15.2 Cancer Immunoediting: Open Questions and Implications for Tumor Immunotherapy 306  
        15.2.1 Manipulating Antitumor T-Cell Immunity 307  
        15.2.2 Adoptive T-Cell Therapy 307  
        15.2.3 Improving Adoptive T-Cell Therapy 309  
        15.2.4 Tumor Vaccines: Improving What is Not Working 310  
        15.2.5 Abrogation or Elimination of Negative Signals 311  
        15.2.6 Reversal of Immunological Tolerance 311  
        15.2.7 Inhibition of Tumor-Associated Immunosuppression 312  
        15.2.8 Hyperactivation or Constitutive Engagement of “Suppressive” Signaling Pathways 313  
     15.3 Conclusions or How Tackling Complex Processes Require Cooperativity 314  
     References 314  
  Chapter 16 Aurora Kinases: A New Target for Anticancer Drug Development 320  
     16.1 Introduction 320  
     16.2 Biology of Aurora Kinase Family 320  
        16.2.1 Aurora Kinase A 321  
        16.2.2 Aurora Kinase B 321  
        16.2.3 Aurora Kinase C 322  
     16.3 Aurora Kinases and Cancer 322  
        16.3.1 Aurora Kinase A and Cancer 322  
        16.3.2 Aurora Kinase B and Cancer 323  
        16.3.3 Aurora Kinase C and Cancer 323  
     16.4 Development of Aurora Kinase Inhibitors 324  
        16.4.1 ZM447439 324  
        16.4.2 Hesperadin 325  
        16.4.3 MK0457 325  
        16.4.4 MLN8054 325  
        16.4.5 Compound 677 325  
        16.4.6 AZD1152 325  
     16.5 Conclusion 325  
     References 326  
  Chapter 17 Emerging Molecular Therapies: Drugs Interfering With Signal Transduction Pathways 329  
     17.1 Introduction 329  
     17.2 Rationale for Targeting Signal Transduction Pathways 329  
     17.3 Strategies for Hitting Signal Transduction Targets 333  
     17.4 Contemporary Drug Development 333  
        17.4.1 New Technologies Enhancing the Efficiency of Drug Discovery and Development 333  
     17.5 Clinical Trial Design for Molecular Therapeutics 337  
        17.5.1 Traditional Clinical Drug Development for Cytotoxic Agents 337  
        17.5.2 Clinical Trial Design for Molecular Therapeutics 337  
        17.5.3 The Importance of Pharmacokinetic and Pharmacodynamic Endpoints 338  
        17.5.4 Invasive and Noninvasive Biomarkers 339  
     17.6 Imatinib as a Paradigm for Cancer Therapy 342  
        17.6.1 Imatinib in CML 342  
        17.6.2 Resistance to Imatinib in CML 342  
        17.6.3 Overcoming Resistance 343  
        17.6.4 Nilotinib 343  
        17.6.5 Dasatinib 343  
     17.7 Imatinib in GIST 344  
        17.7.1 Imatinib Resistance in GIST 344  
     17.8 Targeting ErbB Receptor Signaling 345  
        17.8.1 Targeting EGFR: Small Molecule or Antibody? 345  
        17.8.2 Gefitinib 345  
        17.8.3 Trials in First-Line NSCLC Treatment (INTACT)-1 and (INTACT)-2 346  
        17.8.4 Single Agent Trials 346  
        17.8.5 Erlotinib 346  
        17.8.6 EGFR Mutations and Response to EGFR Tyrosine Kinase Inhibitors 346  
        17.8.7 EGFR Mutations: Not the Whole Story 347  
        17.8.8 Resistance Mutations 347  
     17.9 Anti-EGFR Monoclonal Antibodies 347  
        17.9.1 Cetuximab 347  
        17.9.2 Cetuximab for Squamous Cell Carcinoma of the Head and Neck 348  
        17.9.3 Cetuximab for Colorectal Carcinoma 348  
        17.9.4 Cetuximab in Non-small-Cell Lung Cancer 348  
        17.9.5 Panitumumab 348  
     17.10 Targeting HER2 348  
        17.10.1 Trastuzumab 349  
     17.11 Dual Inhibition of EGFR and HER2 350  
        17.11.1 Lapatinib 350  
        17.11.2 BIBW-2992 and HKI-272 351  
        17.11.3 Canertinib (CI-1033) 351  
        17.11.4 Pertuzumab 351  
     17.12 The IGF-1 Receptor 351  
     17.13 Retinoids—Targeting the PML-RARa Fusion Protein in APL 352  
     17.14 Farnesyl Transferase Inhibitors 352  
        17.14.1 Tipifarnib 352  
     17.15 RAF and MEK Inhibitors 353  
        17.15.1 ISIS 5132/ LErafAON 353  
        17.15.2 CI-1040, PDO325901 and ARRY-142886 353  
     17.16 Phosphatidylinositol 3-Kinase (PI3 Kinase) Pathway Inhibitors 354  
     17.17 Inhibitors of the Mammalian Target of Rapapmycin (mTOR) 354  
        17.17.1 Everolimus 354  
        17.17.2 Temsirolimus 355  
        17.17.3 AP23573 355  
     17.18 Cyclin-Dependent Kinase Inhibitors 356  
     17.19 Inhibitors of HSP90 356  
     17.20 Inhibiting Angiogenesis 358  
        17.20.1 Bevacizumab 358  
        17.20.2 Sunitinib 359  
        17.20.3 Sorafenib 359  
     17.21 Histone Deacetylase Inhibitors 360  
     17.22 Poly ADP-Ribose Polymerase (PARP) Inhibition 361  
     17.23 Targeting Single versus Multiple Signal Transduction Pathways 361  
     17.24 Concluding Remarks 362  
     References 365  
  Chapter 18 Suicide Gene Therapy 378  
     18.1 Introduction 378  
     18.2 Background to Suicide Gene Therapy 378  
     18.3 Vectors in Suicide Gene Therapy 378  
        18.3.1 Nonreplicating Viral Vectors 379  
        18.3.2 Replication-Selective Viruses 379  
        18.3.3 Bacterial Vectors 380  
        18.3.4 Nonviral and Viral/Nonviral Hybrid Vectors 380  
        18.3.5 Targeting Cancer Cells 381  
     18.4 Enzyme/Prodrug Systems for GDEPT 382  
     18.5 Prodrugs and Drugs for Suicide Gene Therapy 383  
     18.6 The Bystander Effect 384  
        18.6.1 Mechanisms of the Bystander Effect 384  
        18.6.2 Immune Effects (in GDEPT) 385  
     18.7 Clinical Evaluation 386  
     18.8 Conclusions 386  
     References 387  
  Chapter 19 Genotypes That Predict Toxicity and Genotypes That Predict Efficacy of Anticancer Drugs 394  
     19.1 Introduction 394  
     19.2 Using mRNA Expression Profiling of DNA Repair Genes to Determine Anticancer Drug Efficacy: Potential Markers of Response to Chemotherapy 394  
        19.2.1 ERCC1 and Cisplatin Resistance 394  
        19.2.1 BRCA1 as a Predictive Marker for Platinum and Antimicrotubule Agents 396  
        19.2.2 Ribonucleotide Reductase 396  
     19.3 Single Nucleotide Polymorphisms in DNA Repair Genes 397  
        19.3.1 XPD SNP 397  
        19.3.2 ERCC1 SNP 398  
        19.3.3 XRCC3 SNPs 398  
     19.4 Conclusions 398  
     References 399  
  Chapter 20 A Personal Account of the Chemoprevention of Breast Cancer: Possible or Not Possible? 402  
     20.1 Introduction 402  
     20.2 ICI 46,474 to Tamoxifen 402  
     20.3 Recognition of SERM Action 403  
     20.4 Preparing to Use Nonsteroidal Antiestrogens as Chemopreventive Agents 403  
     20.5 The Indirect Approach to Breast Cancer Chemoprevention 404  
     20.6 The Indirect Approach to Chemoprevention in Practice 404  
     20.7 The Direct Approach to the Chemoprevention of Breast Cancer 405  
     20.8 The Practice of Chemoprevention 406  
     References 407  
  Appendix A 410  
  Appendix B 414  
  Index 416  


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