Roth Gene-Based Therapies for Cancer

1. Auflage 2010
ISBN: 978-1-4419-6102-0
Verlag: Springer
Format: PDF
Kopierschutz: 1 - PDF Watermark

E-Book, Englisch, 278 Seiten

Reihe: Current Cancer Research

Cancer gene therapy is a novel therapy that targets the underlying genetic defects in the cancer cell. Progress in this field has been rapid and gene therapy promises to further extend personalized cancer treatment. In this volume leading experts have contributed their experience in developing gene therapies for a variety of cancers. Translational gene therapy approaches are emphasized. Chapters include discussions of specific gene delivery technologies as well as their application to various cancers with extensive discussions of ongoing clinical trials. This information should be useful to both students, fellows, and experienced scientists with an interest in this rapidly developing area.

Autoren/Hrsg.

Roth, Jack A.

Inhaltsverzeichnis

1;Foreword;6
2;Contents;8
3;Contributors;10
4;Chapter 1: RNAi: A New Paradigm in Cancer Gene Therapy;16
4.1;1 Introduction;17
4.2;2 Clinical Significance of the RNAi Processing Machinery;18
4.3;3 Clinical Application of RNAi;19
4.4;4 Off-Target Effects;23
4.5;5 RNAi Imaging: Biodistribution and Target Modulation;25
4.6;6 Development of RNAi-Based Gene Therapy: Clinical Trials;26
4.7;7 Future Development;27
4.8;References;28
5;Chapter 2: Gene-Based Therapy for Cancer: Brain Tumors;31
5.1;1 Introduction;31
5.2;2 Replication-Deficient Viral Vectors;32
5.2.1;2.1 Ad-p53;32
5.2.2;2.2 HSVtk/GCV Gene Therapy;34
5.3;3 Oncolytic Viruses;35
5.3.1;3.1 Adenovirus;35
5.3.1.1;3.1.1 ONYX-015;36
5.3.1.2;3.1.2 Delta-24-RGD;37
5.3.2;3.2 Herpes Simplex Virus-1;38
5.3.3;3.3 Reovirus;39
5.3.4;3.4 Measles Virus;40
5.3.5;3.5 Newcastle Disease Virus;40
5.4;4 Future Perspectives;41
5.5;References;42
6;Chapter 3: Gene Therapy of Prostate Cancer;47
6.1;1 Introduction;47
6.2;2 Enzyme/Prodrug Gene Therapy;48
6.2.1;2.1 Enzyme/Prodrug Gene Therapy Using Replication-Defective Adenoviruses;48
6.2.2;2.2 Enzyme/Prodrug Gene Therapy Using Replication-Competent Adenoviruses;50
6.3;3 Vaccine-Based Gene Therapy Strategies;55
6.3.1;3.1 Poxvirus-Based Vaccines;55
6.3.2;3.2 Cell-Based Vaccines;57
6.4;4 Replication-Competent, Oncolytic Adenoviruses;58
6.5;5 Summary;59
6.6;References;60
7;Chapter 4: siRNA Versus shRNA for Personalized Cancer Therapy: Mechanisms and Applications;64
7.1;1 Introduction;65
7.2;2 Personalized Cancer Therapy;65
7.3;3 Mechanisms of RNAi;66
7.3.1;3.1 siRNA;66
7.3.2;3.2 shRNA;68
7.3.2.1;3.2.1 Bifunctional shRNA;69
7.4;4 SiRNA Versus shRNA;70
7.4.1;4.1 Comparative Efficacy;70
7.4.2;4.2 Dicer/Drosha Expression in Cancer and RNAi Effector Suitability;70
7.4.3;4.3 Off-Target Effects;71
7.4.3.1;4.3.1 Specific Off-Target Effects;71
7.4.3.2;4.3.2 Nonspecific Off-Target Effects;71
7.5;5 Delivery Strategies for Clinical Translation;72
7.6;6 Conclusions;73
7.7;References;73
8;Chapter 5: Tumor Suppressor Gene Therapy;76
8.1;1 Tumor Suppressor Gene Therapy;77
8.2;2 Gene Replacement by p53 in Laboratory Studies;78
8.3;3 Clinical Trials of p53 Gene Replacement;79
8.4;4 Gene Replacement in Combination with DNA Damaging Agents;81
8.5;5 Clinical Trials of Tumor Suppressor Gene Replacement Combined with Chemotherapy;82
8.6;6 Clinical Trials of p53 Gene Replacement Combined with Radiation Therapy;82
8.7;7 Systemic Gene Therapy for Metastases;84
8.8;8 Summary and Conclusions;87
8.9;References;88
9;Chapter 6: Targeted Oncolytic Adenovirus for Human Cancer Therapy: Gene-Based Therapies for Cancer;92
9.1;1 Introduction;92
9.2;2 Telomerase Activity for Transcriptional Cancer Targeting;94
9.3;3 Telomerase-Specific Oncolytic Adenovirus for Cancer Therapeutics;94
9.3.1;3.1 Structure of hTERT Promoter-Driven Oncolytic Adenovirus;94
9.3.2;3.2 Preclinical Studies of hTERT Promoter-Driven Oncolytic Adenovirus;95
9.3.3;3.3 Immune Activation by hTERT Promoter-Driven Oncolytic Adenovirus;98
9.4;4 Telomerase-Specific Oncolytic Adenovirus for Cancer Diagnostics;99
9.4.1;4.1 hTERT Promoter-Driven GFP-Expressing Oncolytic Adenovirus;99
9.4.2;4.2 Ex vivo Imaging of Human Circulating Tumor Cells with GFP Fluorescence;99
9.4.3;4.3 In Vivo Imaging of Lymph Node Micrometastasis with GFP Fluorescence;100
9.5;5 Clinical Application of Telomerase-Specific Oncolytic Adenovirus;101
9.6;6 Conclusions and Perspectives;101
9.7;References;103
10;Chapter 7: Gene Therapy for Malignant Pleural Mesothelioma;107
10.1;1 Background;107
10.2;2 MPM as a Target for Gene Therapy;108
10.3;3 Preclinical Investigations;108
10.3.1;3.1 Induction of Apoptosis;108
10.3.2;3.2 Antiangiogenesis;110
10.3.3;3.3 Suicide-Gene Therapy;110
10.3.4;3.4 Immunogene Therapy;112
10.3.5;3.5 Replicating, Tumor-Selective Oncolytic Viral Vectors;113
10.4;4 Clinical Investigations;114
10.4.1;4.1 Suicide Gene Therapy;114
10.4.2;4.2 Cytokine Gene Therapy;116
10.5;5 Summary;118
10.6;References;119
11;Chapter 8: Mesenchymal Stem/Stromal Cells as Cellular Vehicles for Tumor Targeting;124
11.1;1 Introduction;124
11.1.1;1.1 Tumor Cell-Centric View on Tumor Development;124
11.1.2;1.2 Stroma is a Common Ground for Numerous Cancers;125
11.1.3;1.3 Role of Fibroblasts and Stromal Precursors;128
11.2;2 Tropism of MSC for Wounds and Tumors;129
11.2.1;2.1 But Which Cell in the Stroma to Target;130
11.2.2;2.2 Rationale for Targeting Tumors Using Stromal Precusor Cells;131
11.2.3;2.3 Migratory Factors;132
11.3;3 Use of Stem Cells as Cellular Vehicles to Target Tumors;133
11.3.1;3.1 MSC as Cell Vehicles for Cancer;135
11.4;4 Interferons;136
11.5;5 Interleukins;137
11.6;6 Conditionally Replication Adenoviral Vectors;138
11.7;7 Chemokines and Growth Factor Antagonists;139
11.8;8 Suicide Genes;139
11.9;9 Tumor Necrosis Factor-Related Apoptosis Inducing Ligand;140
11.10;10 Alternative Mesenchymal Tissues as Sources for Anticancer Therapies;140
11.11;11 Conclusions;141
11.12;References;142
12;Chapter 9: Retargeting Adenovirus for Cancer Gene Therapy;151
12.1;1 Introduction;151
12.2;2 Adenovirus Life Cycle and Genomic Organization;152
12.3;3 Strategies for Ad-Based Cancer Gene Therapy;153
12.3.1;3.1 Cancer Gene Therapy Vectors;153
12.3.2;3.2 Immunotherapy Vectors;153
12.3.3;3.3 Virotherapy Vectors;154
12.4;4 A Need for Retargeted Adenovirus-Based Vectors for Cancer Therapy;154
12.5;5 Transductional Targeting;155
12.5.1;5.1 Adapter-Based Targeting;155
12.5.2;5.2 Genetic Modifications;156
12.6;6 Cellular Control of Ad Vector Gene Expression;156
12.6.1;6.1 Transcriptional Targeting;157
12.6.2;6.2 Translational Targeting;158
12.6.3;6.3 Functional Complementation;158
12.7;7 Adjunct Technologies for Delivery;159
12.8;8 Future Directions and Conclusions;159
12.9;References;161
13;Chapter 10: Lentiviruses: Vectors for Cancer Gene Therapy;164
13.1;1 Introduction;164
13.2;2 Lentiviruses;166
13.2.1;2.1 Lentiviral Genome and Structure;166
13.2.2;2.2 Lentiviral Life Cycle;167
13.3;3 HIV-1 Derived Lentiviral Vector;168
13.3.1;3.1 Lentiviral Vector Packaging System;169
13.3.2;3.2 Design and Improvement of Lentiviral Transfer Vector;169
13.3.3;3.3 Non-HIV-1 Derived Lentiviral Vectors;172
13.3.4;3.4 Pseudotyping Lentiviral Vector;173
13.3.5;3.5 Production of Lentiviral Vector;173
13.4;4 Applications of Lentiviral Vector in Cancer Therapy;175
13.4.1;4.1 Suicide Gene Therapy;175
13.4.2;4.2 Lentiviral Immunotherapy for Cancer;175
13.4.3;4.3 Gene Replacement and Gene Silencing;177
13.4.4;4.4 Antiangiogenesis Therapy;177
13.4.5;4.5 Myeloprotection Against Chemotherapeutics;178
13.5;5 Clinical Trials of Lentiviral Vectors;178
13.6;6 Conclusion;179
13.7;References;181
14;Chapter 11: Interleukin-24 Gene Therapy for Melanoma;189
14.1;1 Biology of IL-24 a Tumor Suppressor/Cytokine;189
14.1.1;1.1 Tumor Suppressor Properties;189
14.1.2;1.2 Cytokine Properties;192
14.2;2 Expression of IL-24 in Melanocytes and Melanoma;193
14.3;3 Re-expression of the Tumor Suppressor;194
14.4;4 Clinical Experience with Ad mda-7/IL-24;196
14.4.1;4.1 Metastatic Melanoma;196
14.4.2;4.2 Phase I/II intratumoral Ad-mda-7/IL-24 Gene Transfer in Patients with Advanced Solid Tumors;197
14.4.3;4.3 Phase II Intratumoral Injection of Ad-mda-7/IL-24 in Patients with Advanced Melanoma;198
14.4.3.1;4.3.1 Clinical Results;199
14.4.3.2;4.3.2 Laboratory Results;199
14.4.3.2.1;Induction of Pro-apoptotic and Anti-proliferative Effects in the Ad-mda-7/IL-24 Injected Melanoma in Transit Lesions;199
14.4.3.2.2;Effects of Ad-mda-7/IL-24 on the Peripheral Immune System;200
14.5;5 Other Preclinical Studies Using Viral Delivery of IL-24;201
14.6;6 Systemic Delivery of Non-viral Nanoparticle-Based Gene Delivery Systems;202
14.6.1;6.1 Preclinical Studies Using DOTAP:chol mda7/IL-24;202
14.6.2;6.2 Current Status of Non-viral Nanoparticles-Based Cancer Gene Therapy Clinical Trials;203
14.7;7 Conclusion;204
14.8;References;205
15;Chapter 12: Herpes Simplex Virus 1 for Cancer Therapy;211
15.1;1 Herpes Simplex Virus 1 for Cancer Therapy;211
15.2;2 Herpes Simplex Virus 1;212
15.3;3 Thymidine Kinase (UL23/ICP36);213
15.4;4 ICP 34.5 (RL1);214
15.5;5 Ribonucleotide Reductase (ICP 6);216
15.6;6 ICP 47;216
15.7;7 HSV1 Viruses in Clinical Trials for Cancer;217
15.7.1;7.1 G207;217
15.7.2;7.2 HSV1716;219
15.7.3;7.3 NV1020 (RV7020);225
15.7.4;7.4 HF10;226
15.7.5;7.5 OncoVex GM-CSF;228
15.8;8 The Future of Oncolytic HSV1 Cancer Therapy;229
15.9;9 Conclusion;231
15.10;References;231
16;Chapter 13: Telomerase as a Target for Cancer Therapeutics;239
16.1;1 Telomeres;239
16.2;2 Telomerase;241
16.3;3 Telomerase and Early Cancer Detection;242
16.4;4 Antitelomerase Cancer Therapy;243
16.5;5 Telomerase Immunotherapy;244
16.6;6 GRN163L (Imetelstat), Oligonucleotide Enzyme Inhibitor;247
16.7;7 Telomerase-Associated Gene Therapy;250
16.8;8 Ad-hTR-NTR: A Telomerase Targeted Adenoviral Suicide Gene Therapy Vector;250
16.9;9 Telomerase Specific Oncolytic Virus;250
16.10;10 Concluding Remarks;251
16.11;References;252
17;Chapter 14: Gene Therapy for Sarcoma;258
17.1;1 Introduction;258
17.2;2 Cytogenetics of Soft Tissue Sarcoma;259
17.3;3 Expression Signatures;263
17.4;4 Gene Therapy;266
17.5;5 Nonviral Vectors;266
17.6;6 Viral Vectors;267
17.7;7 Summary;269
17.8;References;270
18;Index;276