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Gene-Based Therapies for Cancer

:	Jack A. Roth
:	Jack A. Roth
:	Gene-Based Therapies for Cancer
:	Springer-Verlag
:	9781441961020
:	1
:	CHF 132.60
:

:	Nichtklinische Fächer
:	English

:	278
:	Wasserzeichen/DRM
:	PC/MAC/eReader/Tablet
:	PDF

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.

	Foreword	6
	Contents	8
	Contributors	10
	Chapter 1: RNAi: A New Paradigm in Cancer Gene Therapy	16
	1 Introduction	17
	2 Clinical Significance of the RNAi Processing Machinery	18
	3 Clinical Application of RNAi	19
	4 Off-Target Effects	23
	5 RNAi Imaging: Biodistribution and Target Modulation	25
	6 Development of RNAi-Based Gene Therapy: Clinical Trials	26
	7 Future Development	27
	References	28
	Chapter 2: Gene-Based Therapy for Cancer: Brain Tumors	31
	1 Introduction	31
	2 Replication-Deficient Viral Vectors	32
	2.1 Ad-p53	32
	2.2 HSVtk/GCV Gene Therapy	34
	3 Oncolytic Viruses	35
	3.1 Adenovirus	35
	3.1.1 ONYX-015	36
	3.1.2 Delta-24-RGD	37
	3.2 Herpes Simplex Virus-1	38
	3.3 Reovirus	39
	3.4 Measles Virus	40
	3.5 Newcastle Disease Virus	40
	4 Future Perspectives	41
	References	42
	Chapter 3: Gene Therapy of Prostate Cancer	47
	1 Introduction	47
	2 Enzyme/Prodrug Gene Therapy	48
	2.1 Enzyme/Prodrug Gene Therapy Using Replication-Defective Adenoviruses	48
	2.2 Enzyme/Prodrug Gene Therapy Using Replication-Competent Adenoviruses	50
	3 Vaccine-Based Gene Therapy Strategies	55
	3.1 Poxvirus-Based Vaccines	55
	3.2 Cell-Based Vaccines	57
	4 Replication-Competent, Oncolytic Adenoviruses	58
	5 Summary	59
	References	60
	Chapter 4: siRNA Versus shRNA for Personalized Cancer Therapy: Mechanisms and Applications	64
	1 Introduction	65
	2 Personalized Cancer Therapy	65
	3 Mechanisms of RNAi	66
	3.1 siRNA	66
	3.2 shRNA	68
	3.2.1 Bifunctional shRNA	69
	4 SiRNA Versus shRNA	70
	4.1 Comparative Efficacy	70
	4.2 Dicer/Drosha Expression in Cancer and RNAi Effector Suitability	70
	4.3 Off-Target Effects	71
	4.3.1 Specific Off-Target Effects	71
	4.3.2 Nonspecific Off-Target Effects	71
	5 Delivery Strategies for Clinical Translation	72
	6 Conclusions	73
	References	73
	Chapter 5: Tumor Suppressor Gene Therapy	76
	1 Tumor Suppressor Gene Therapy	77
	2 Gene Replacement by p53 in Laboratory Studies	78
	3 Clinical Trials of p53 Gene Replacement	79
	4 Gene Replacement in Combination with DNA Damaging Agents	81
	5 Clinical Trials of Tumor Suppressor Gene Replacement Combined with Chemotherapy	82
	6 Clinical Trials of p53 Gene Replacement Combined with Radiation Therapy	82
	7 Systemic Gene Therapy for Metastases	84
	8 Summary and Conclusions	87
	References	88
	Chapter 6: Targeted Oncolytic Adenovirus for Human Cancer Therapy: Gene-Based Therapies for Cancer	92
	1 Introduction	92
	2 Telomerase Activity for Transcriptional Cancer Targeting	94
	3 Telomerase-Specific Oncolytic Adenovirus for Cancer Therapeutics	94
	3.1 Structure of hTERT Promoter-Driven Oncolytic Adenovirus	94
	3.2 Preclinical Studies of hTERT Promoter-Driven Oncolytic Adenovirus	95
	3.3 Immune Activation by hTERT Promoter-Driven Oncolytic Adenovirus	98
	4 Telomerase-Specific Oncolytic Adenovirus for Cancer Diagnostics	99
	4.1 hTERT Promoter-Driven GFP-Expressing Oncolytic Adenovirus	99
	4.2 Ex vivo Imaging of Human Circulating Tumor Cells with GFP Fluorescence	99
	4.3 In Vivo Imaging of Lymph Node Micrometastasis with GFP Fluorescence	100
	5 Clinical Application of Telomerase-Specific Oncolytic Adenovirus	101
	6 Conclusions and Perspectives	101
	References	103
	Chapter 7: Gene Therapy for Malignant Pleural Mesothelioma	107
	1 Background	107
	2 MPM as a Target for Gene Therapy	108
	3 Preclinical Investigations	108
	3.1 Induction of Apoptosis	108
	3.2 Antiangiogenesis	110
	3.3 Suicide-Gene Therapy	110
	3.4 Immunogene Therapy	112
	3.5 Replicating, Tumor-Selective Oncolytic Viral Vectors	113
	4 Clinical Investigations	114
	4.1 Suicide Gene Therapy	114
	4.2 Cytokine Gene Therapy	116
	5 Summary	118
	References	119
	Chapter 8: Mesenchymal Stem/Stromal Cells as Cellular Vehicles for Tumor Targeting	124
	1 Introduction	124
	1.1 Tumor Cell-Centric View on Tumor Development	124
	1.2 Stroma is a Common Ground for Numerous Cancers	125
	1.3 Role of Fibroblasts and Stromal Precursors	128
	2 Tropism of MSC for Wounds and Tumors	129
	2.1 But Which Cell in the Stroma to Target	130
	2.2 Rationale for Targeting Tumors Using Stromal Precusor Cells	131
	2.3 Migratory Factors	132
	3 Use of Stem Cells as Cellular Vehicles to Target Tumors	133
	3.1 MSC as Cell Vehicles for Cancer	135
	4 Interferons	136
	5 Interleukins	137
	6 Conditionally Replication Adenoviral Vectors	138
	7 Chemokines and Growth Factor Antagonists	139
	8 Suicide Genes	139
	9 Tumor Necrosis Factor-Related Apoptosis Inducing Ligand	140
	10 Alternative Mesenchymal Tissues as Sources for Anticancer Therapies	140
	11 Conclusions	141
	References	142
	Chapter 9: Retargeting Adenovirus for Cancer Gene Therapy	151
	1 Introduction	151
	2 Adenovirus Life Cycle and Genomic Organization	152
	3 Strategies for Ad-Based Cancer Gene Therapy	153
	3.1 Cancer Gene Therapy Vectors	153
	3.2 Immunotherapy Vectors	153
	3.3 Virotherapy Vectors	154
	4 A Need for Retargeted Adenovirus-Based Vectors for Cancer Therapy	154
	5 Transductional Targeting	155
	5.1 Adapter-Based Targeting	155
	5.2 Genetic Modifications	156
	6 Cellular Control of Ad Vecto