Meir CNS Cancer

Models, Markers, Prognostic Factors, Targets, and Therapeutic Approaches
1. Auflage 2009
ISBN: 978-1-60327-553-8
Verlag: Humana Press
Format: PDF
Kopierschutz: 1 - PDF Watermark

E-Book, Englisch, 1284 Seiten

Reihe: Cancer Drug Discovery and Development

Cancers of the central nervous system are among the most lethal of human neoplasms. They are recalcitrant to even intensive multimodality therapies that include surgery, radiotherapy, and chemotherapy. Moreover, especially in children, the consequences of these therapies can itself be devastating and involve serious cognitive and developmental disorders. It is small wonder that such cancers have come under the intense scrutiny of each of the subspecialties of clinical care and investigation as well as attracting some of the best basic research scientists. Their joint efforts are gradually peeling away the mysteries surrounding the genesis and progression of these tumors and inroads are being steadily made into understanding why they resist therapies. This makes it an especially opportune time to assemble some of the best investigators in the field to review the ‘‘state of the art’’ in the various arenas that comprise the assault on CNS tumors. The breadth of this effort by the clinical and basic neuro-oncology community is quite simply amazing. To a large extent, it evolves from the knowledge of the human genome and its regulation that has been hard won over the past two decades.

Autoren/Hrsg.

Meir, Erwin G. van

Inhaltsverzeichnis

1;Cancer Drug Discovery and Development;2
1.1;CNS Cancer;3
1.2;Foreword;6
1.3;Preface;8
1.4;Editor;10
1.5;Contents;12
1.6;Contributors;17
1.7;Color Plates;26
2;Part 1: Animal Models for Central Nervous Tumors;39
3;Modeling Gliomas Using PDGF-Expressing Retroviruses;40
3.1;1.1 The Utility of Animal Glioma Models;41
3.2;1.2 Comparing Retroviral Glioma Models to Other Model Systems;41
3.2.1;1.2.1 Transplantation of Glioma Cell-Lines;42
3.2.2;1.2.2 Transplantation of Primary Glioma Cells or Cancer Stem Cells;43
3.2.3;1.2.3 Glioma Models Using Genetically Engineered Mice (GEM);43
3.2.4;1.2.4 Retroviral Glioma Models;45
3.2.4.1;1.2.4.1 Using Retroviruses to Deliver Genetic Lesions to Discrete Cell Populations at a Specific Place and Time;45
3.2.4.2;1.2.4.2 PDGF as a Link Between Glial Progenitors and Gliomas;47
3.2.4.3;1.2.4.3 PDGF Retroviruses Drive the Formation of Tumors That Closely Resemble Human Gliomas;48
3.2.4.4;1.2.4.4 PDGF Drives Adult Glial Progenitors to form Malignant Gliomas;49
3.2.4.5;1.2.4.5 Using Retroviruses to Test the Effects of Multiple Genetic Lesions;52
3.2.4.6;1.2.4.6 Using Retroviral Models to Study Glioma Infiltration;52
3.2.4.7;1.2.4.7 Using Retroviral Models to Study Interactions Within the Brain Microenvironment;54
3.2.4.8;1.2.4.8 Using Retroviral Models for Preclinical Studies;56
3.3;References;59
4;Modeling Brain Tumors Using Avian Retroviral Gene Transfer;65
4.1;2.1 History;66
4.2;2.2 RCAS;67
4.3;2.3 Retroviral Life Cycle;68
4.4;2.4 Tv-a Transgenic Mice;70
4.5;2.5 Modeling Brain Tumors with RCAS/tv-a;71
4.5.1;2.5.1 Gliomas;72
4.5.2;2.5.2 Loss of Function, Knockouts, and Cre/lox;72
4.5.3;2.5.3 Medulloblastomas - SHH Signaling;74
4.6;2.6 Imaging, Stem Cell Niches, and Preclinical Trials;75
4.7;References;76
5;Using Neurofibromatosis Type 1 Mouse Models to Understand Human Pediatric Low-Grade Gliomas;80
5.1;3.1 Pediatric Low-Grade Glioma;81
5.2;3.2 Neurofibromatosis Type 1;82
5.2.1;3.2.1 NF1 Clinical Features;82
5.2.2;3.2.2 Brain Tumors in NF1;82
5.3;3.3 Mouse Models of NF1-Associated Optic Glioma;83
5.3.1;3.3.1 Growth Regulatory Pathways;83
5.3.2;3.3.2 Tumor Microenvironment;85
5.3.3;3.3.3 Preclinical Therapeutic Studies;88
5.4;3.4 Future Directions;90
5.5;References;91
6;Transgenic Mouse Models of CNS Tumors: Using Genetically Engineered Murine Models to Study the Role of p21-Ras in Glioblastoma Multiforme;95
6.1;4.1 Introduction;96
6.2;4.2 Embryonic Stem Cell Transgenesis to Generate Mouse Models;96
6.3;4.3 Genetically Engineered Murine Mouse Models (GEMs) of GBM;98
6.4;4.4 GFAP:12 V-HaRas Astrocytoma Model: Characterization of RasD7, RasB8;99
6.5;4.5 Study of Cooperative Interactions Between Ras Overexpression and Other Known Genetic Alterations in Human Astrocytomas;103
6.6;4.6 Identifying Novel GBM Modifier Genes Using the RasB8 GEM and Gene-Trapping;105
6.7;4.7 Ontogeny of Astrocytomas;107
6.8;4.8 Conclusions;108
6.9;References;109
7;Pten-Deficient Mouse Models for High-Grade Astrocytomas;111
7.1;5.1 Introduction;112
7.2;5.2 Pten-Null or Akt-Activated Mouse Models of High-Grade Astrocytoma;113
7.3;5.3 Pten-Heterozygous Mouse Models of High-Grade Astrocytoma;116
7.4;5.4 Discussion;118
7.5;References;122
8;The Nf1-/+; Trp53-/+cis Mouse Model of Anaplastic Astrocytoma and Secondary Glioblastoma: Dissecting Genetic Susceptibility to Brain Cancer;127
8.1;6.1 Introduction;128
8.2;6.2 Clinical History, Pathology, and Genetics of Astrocytomas;128
8.3;6.3 The NPcis Mouse Model of Astrocytoma/Glioblastoma;132
8.3.1;6.3.1 Histology of NPcis Astrocytomas;134
8.3.2;6.3.2 Molecular Biology of NPcis Astrocytomas;135
8.3.3;6.3.3 Tumor Cell Lines Derived from NPcis Astrocytomas;136
8.4;6.4 Factors Affecting Astrocytoma Susceptibility in NPcis Mice;137
8.4.1;6.4.1 The Effect of Parental Origin and Offspring Sex on NPcis Astrocytomas;137
8.4.2;6.4.2 The Effect of Background Polymorphisms on NPcis Astrocytomas;141
8.5;6.5 Application of the NPcis Model of Astrocytoma;142
8.5.1;6.5.1 Advantages of the NPcis Astrocytoma Model;142
8.5.2;6.5.2 Limitations of the NPcis Astrocytoma Model;144
8.6;6.6 Summary;146
8.7;References;147
9;Modeling Astrocytomas in a Family of Inducible Genetically Engineered Mice: Implications for Preclinical Cancer Drug Development;153
9.1;7.1 Introduction;154
9.2;7.2 In Vivo Modeling of Astrocytomas in Genetically Engineered Mice;155
9.2.1;7.2.1 Overview of Genetic Modeling of Diffuse Gliomas;155
9.2.2;7.2.2 Conditional, Inducible GEM of Astrocytomas;163
9.2.3;7.2.3 The Future of GEM Astrocytoma Models;168
9.3;7.3 Astrocytoma GEM Application in Translational and Preclinical Research;170
9.4;References;174
10;Human Brain Tumor Cell and Tumor Tissue Transplantation Models;180
10.1;8.1 Cell Culture-Based Approaches;181
10.2;8.2 Xenograft-Based Tumor Propagation;184
10.3;8.3 Intracranial vs. Subcutaneous Tumor Therapy Response Experiments;186
10.4;8.4 The Impact of Bioluminescence Imaging;188
10.5;8.5 Human Tumor Panels and Pre-Clinical Therapeutic Testing of Multiple Tumors;191
10.6;References;192
11;Transformed Human Brain Cells in Culture as a Model for Brain Tumors;195
11.1;9.1 Introduction;196
11.2;9.2 Early Developments;198
11.3;9.3 Modifiers of Transformation and Tumor Behavior;201
11.4;9.4 Answers and More Questions;204
11.5;9.5 New Approaches;207
11.6;9.6 Conclusions;208
11.7;References;209
12;Rat Glioma Models for Preclinical Evaluation of Novel Therapeutic and Diagnostic Modalities;213
12.1;10.1 Introduction;214
12.2;10.2 9L Gliosarcoma;217
12.3;10.3 T9 Glioma;221
12.4;10.4 C6 Glioma;222
12.5;10.5 F98 Gliomas;223
12.6;10.6 RG2 (or D74) Glioma;225
12.7;10.7 Avian Sarcoma Virus-Induced and RT-2 Gliomas;226
12.8;10.8 CNS-1 Glioma;227
12.9;10.9 BT4C Glioma;227
12.10;10.10 Concluding Comments;228
12.11;References;229
13;Neuro-oncogenesis Induced by Nitroso Compounds in Rodents and Strain-Specific Genetic Modifiers of Predisposition;238
13.1;11.1 Introduction;239
13.2;11.2 The Neuro-Oncogenic Effect of ENU and MNU;240
13.3;11.3 Characteristics of ENU- and MNU-Induced Nervous System Tumors;241
13.3.1;11.3.1 Histological Classification;241
13.3.2;11.3.2 Genetic Alterations;242
13.4;11.4 Determinants of ENU- and MNU-Induced Neuro-oncogenesis;243
13.4.1;11.4.1 Developmental Stage of the Nervous System at ENU Exposure;243
13.4.2;11.4.2 Doses and Route of Administration;244
13.4.3;11.4.3 Rodent Species and Strain;244
13.5;11.5 Genetics of Susceptibility and Resistance to ENU-Induced Neuro-oncogenesis and Analyses of the Underlying Phenotypes;245
13.5.1;11.5.1 Inheritance of Susceptibility to ENU-Induced MPNST Development;247
13.5.2;11.5.2 Identification and Characterization of Gene Loci Involved in Susceptibility or Resistance to ENU-Induced MPNST Development;247
13.5.3;11.5.3 Phenotypic Analyses of Effector Mechanisms Underlying Differential MPNST Risk;250
13.6;11.6 Conclusions;253
13.7;References;255
14;The Murine GL261 Glioma Experimental Model to Assess Novel Brain Tumor Treatments;258
14.1;12.1 The Murine GL261 Glioma Experimental Model;259
14.2;12.2 The Murine GL261 Glioma Experimental Model: Validation Studies for a Predictive Preclinical Model;260
14.3;12.3 Neuropathology;262
14.4;12.4 Tumor Biology;264
14.4.1;12.4.1 Invasion, Angiogenesis, and Hypoxia;264
14.4.2;12.4.2 Signaling Pathways;266
14.5;12.5 Neuroimaging and Neuroradiology;267
14.6;12.6 Significance of GL261 Glioma Animal Model for Use as a Predictive Preclinical Model;268
14.7;References;270
15;Spontaneous Occurrence of Brain Tumors in Animals: Opportunities as Preclinical Model Systems;273
15.1;13.1 Introduction;274
15.2;13.2 Drosophila and Cancer Research;275
15.2.1;13.2.1 Drosophila Brain Tumor (brat) Gene;276
15.3;13.3 Zebrafish: A New Model of Nervous System Tumorigenesis?;280
15.4;13.4 Mouse and Rat Models of Brain Tumors;281
15.4.1;13.4.1 The 4C8 Mouse Glioma Syngeneic Graft Model;281
15.4.2;13.4.2 The Spontaneous VM/Dk Murine Astrocytoma;282
15.4.2.1;13.4.2.1 Cytological Characteristics;282
15.4.2.2;13.4.2.2 Biological Characteristics;282
15.4.3;13.4.3 Rat Brain Tumor Models;283
15.5;13.5 Spontaneous Brain Tumors in Dogs;284
15.5.1;13.5.1 Epidemiology and Pathology;285
15.5.1.1;13.5.1.1 Canine Meningiomas;287
15.5.1.2;13.5.1.2 Canine Astrocytomas;288
15.5.1.3;13.5.1.3 Canine Glioblastoma Multiforme;289
15.5.1.4;13.5.1.4 Canine Oligodendrogliomas;294
15.5.1.5;13.5.1.5 Canine Choroid Plexus Papillomas;294
15.5.2;13.5.2 Prognosis and Treatment for Canine CNS Tumors;294
15.5.3;13.5.3 Canine Brain Tumor Experimental Treatment Trials;298
15.5.3.1;13.5.3.1 Immunotherapy;298
15.5.3.2;13.5.3.2 Gene Therapy;298
15.5.3.3;13.5.3.3 Convection-Enhanced Delivery;298
15.5.4;13.5.4 Canine Glioma Cell Lines;299
15.5.5;13.5.5 Problems and Challenges with the Use of Spontaneous Canine Brain Tumors;300
15.6;13.6 Summary;300
15.7;References;301
16;Part 2: Prognostic Factors and Biomarkers;311
17;p53 Pathway Alterations in Brain Tumors;312
17.1;14.1 Introduction;313
17.2;14.2 The p53 Family;314
17.3;14.3 p53 Functions: Intracellular Effects;314
17.3.1;14.3.1 p53 and Cell Cycle Arrest;315
17.3.2;14.3.2 p53 and Apoptosis;316
17.3.3;14.3.3 p53 Regulation of Cellular Senescence;317
17.3.4;14.3.4 p53 and the Mechanisms Maintaining Genomic Integrity;318
17.3.5;14.3.5 p53 and MicroRNA;319
17.3.6;14.3.6 p53 and Invasion/Motility;319
17.3.7;14.3.7 p53 in Differentiation, Development, and Aging;319
17.3.8;14.3.8 p53 and Aerobic Respiration and Glycolysis;320
17.4;14.4 p53 Function: Effects on the Tumor Microenvironment (p53 Extracellular Effects);320
17.4.1;14.4.1 p53 and Angiogenesis;321
17.4.2;14.4.2 p53 and the Immune Response;322
17.5;14.5 p53 Regulation;322
17.5.1;14.5.1 The p14ARF/MDM2/p53 Pathway;323
17.5.2;14.5.2 Phosphorylation;324
17.5.3;14.5.3 Acetylation;325
17.5.4;14.5.4 Subcellular Localization;325
17.6;14.6 TP53 Mutations in Brain Tumors;326
17.6.1;14.6.1 p53 Mutation Spectrum in Brain Tumors;326
17.6.2;14.6.2 Mutation Sites;328
17.6.3;14.6.3 Mechanism of Action of p53 Mutants;328
17.7;14.7 Mutant p53 as a Therapeutic Target;330
17.7.1;14.7.1 Reactivation of Mutant p53 by Structural Manipulations and Peptides;330
17.7.2;14.7.2 Small Molecules That Target Mutant p53;330
17.7.3;14.7.3 Gene Delivery of wt p53;331
17.7.4;14.7.4 Viral Therapy Specific for Tumor Cells with Mutant p53;331
17.8;14.8 Summary;332
17.9;References;332
18;The PTEN/PI3 Kinase Pathway in Human Glioma;344
18.1;15.1 Introduction;345
18.2;15.2 Pathway Activation: PI3K Signaling and Downstream Effectors;346
18.2.1;15.2.1 Class 1 PI3Ks;346
18.3;15.3 Upstream Activation of PI3K by RTK Signaling;348
18.3.1;15.3.1 Epidermal Growth Factor Receptor;349
18.3.2;15.3.2 Platelet-Derived Growth Factor Receptor;349
18.3.3;15.3.3 Receptor Co-activation as a Mechanism of Therapeutic Resistance in Glioma;350
18.3.4;15.3.4 Ras;351
18.4;15.4 Regulation of Downstream PI3K Effectors;351
18.5;15.5 Mouse Models Defining the Function of Class 1 PI3Ks;354
18.6;15.6 Pathway Inhibition: PTEN;355
18.6.1;15.6.1 Loss of Heterozygosity of Chromosome 10 and the Search for Tumor Suppressor Genes;355
18.6.2;15.6.2 PTEN Discovery and Its Link to Genetic Syndromes;356
18.6.3;15.6.3 Lipid Phosphatase-Specific Functions of PTEN;357
18.6.4;15.6.4 Protein Phosphatase-Specific Functions of PTEN;358
18.6.5;15.6.5 Non-enzymatic Functions of PTEN;358
18.7;15.7 PTEN in Glioma Biology: Primary vs Secondary Glioma;359
18.8;15.8 PTEN Involvement in Brain Tumor Stem Cells;361
18.9;15.9 Transcriptional Regulation;362
18.10;15.10 Inactivation Mechanisms of PTEN;364
18.10.1;15.10.1 PTEN Loss and Mutation Spectrum in Glioma;364
18.10.2;15.10.2 Modulation of PTEN Function by Protein Modifications;364
18.10.3;15.10.3 MicroRNA Regulation of PTEN Expression;366
18.11;15.11 PTEN Localization;366
18.12;15.12 Other Regulators of Akt Activity;367
18.13;15.13 Mouse Glioma Models and PTEN Involvement;367
18.14;15.14 Therapeutic Intervention and Conditions for Resistance in Glioma and Breast Cancer: PTEN as a Marker for Drug Response and Resistance;368
18.15;15.15 Conclusions;369
18.16;References;370
19;Value of 1p/19q and Other LOH Markers for Brain Tumor Diagnosis, Prognosis, and Therapy;387
19.1;16.1 Introduction;388
19.2;16.2 1p/19q Loss Is Associated with Response to Therapy in Grade III Gliomas;388
19.3;16.3 Is There a Common Prognostic Denominator in GBM and ODG on Chromosome 1p?;389
19.4;16.4 The Search for 1p Glioma Suppressor Genes;390
19.5;16.5 The Search for 19q Glioma Suppressor Genes;391
19.6;16.6 Fine Mapping of the Deletions in the 1p Arm Reveals that Loss of the Centromeric 1p Region/Area Correlates with Survival in ODG and GBM;392
19.7;16.7 Gene Mapping Within the Chromosome 1 Pericentric Duplication;393
19.8;16.8 ROC Analysis for 1p and Prognosis Shows that N2/N2N Analysis Is Superior to Histology;394
19.9;16.9 An Oncogenic Role of Notch2 in Gliomagenesis?;396
19.10;16.10 Conclusion;397
19.11;References;398
20;Discovery of Genetic Markers for Brain Tumors by Comparative Genomic Hybridization;401
20.1;17.1 Historical Perspective;401
20.2;17.2 General Methodology;403
20.3;17.3 Interpretation of aCGH Data;407
20.4;17.4 Strategy for Identifying Genetic Markers with Clinical Relevance Using Array CGH;408
20.5;17.5 New Insights in Primary Brain Tumors Using Array CGH;412
20.6;17.6 Array CGH in Cancer Subgroup and Gene Discovery;416
20.7;17.7 Useful Resources;418
20.8;References;419
21;Genomic Identification of Significant Targets in Brain Cancer;423
21.1;18.1 Introduction;424
21.2;18.2 Key Features of the GISTIC Algorithm;426
21.3;18.3 The Four Stages of the GISTIC: A Detailed View;427
21.4;18.4 Application of GISTIC to Glioma;430
21.5;18.5 Application of GISTIC to Other Cancers;435
21.6;18.6 Limitations and Future Modifications of the GISTIC Algorithm;436
21.7;References;438
22;Oncomodulatory Role of the Human Cytomegalovirus in Glioblastoma;442
22.1;19.1 Human Cytomegalovirus Background;444
22.1.1;19.1.1 HCMV Is Widely Prevalent and Persistently Infects Adult Human Stem Cells;444
22.1.2;19.1.2 HCMV and Human Malignant Gliomas;444
22.2;19.2 Oncomodulatory Properties of HCMV and Their Contribution to Glioma Pathogenesis;445
22.2.1;19.2.1 The Role of Inflammatory Chemokines and Chemokine Receptors;445
22.2.2;19.2.2 HCMV Immediate-Early (IE) Gene Products Dysregulate Cell Cycle Controls, Are Mutagenic, Are Anti-Apoptotic, and Promote Oncogenic Transformation;446
22.2.3;19.2.3 HCMV Infection Modulates Cell Proliferation and Cell Survival Signaling Pathways;447
22.2.4;19.2.4 HCMV Infection Modulates Cellular Pathways that Promote Cell Migration and Invasion;447
22.2.5;19.2.5 HCMV Promotes Angiogenesis;448
22.2.6;19.2.6 HCMV Strain Variability and Gene Expression Patterns Influence Viral Neurotropism;448
22.3;19.3 HCMV Reactivation in Patients with Malignant Gliomas: The Role of the Immune System and Lessons from Animal Models;449
22.3.1;19.3.1 The Impact of the Immunosuppressed Status of GBM Patients on HCMV Reactivation;449
22.3.2;19.3.2 Reactivation of CMV During Neural Precursor Differentiation: Evidence from Mouse Models;450
22.3.3;19.3.3 HCMV Infection Can Arrest Differentiation of Stem Cells;450
22.4;19.4 The Glioma Cell of Origin: The Role of Glioma Stem-Like Cells;450
22.4.1;19.4.1 Glioma Stem Cells;450
22.4.2;19.4.2 Evidence for a Role of HCMV IE1 Expression in Glioma Stem-Like Cells;452
22.5;19.5 The Role of PDGF/PDGFRalpha Signaling in Gliomagenesis;453
22.5.1;19.5.1 The PDGF/PDGFR System Is Genetically Altered in GBMs;453
22.5.2;19.5.2 PDGFRalpha Is a Required Cellular Receptor for HCMV;454
22.6;19.6 Evidence in Support of a Role for HCMV-Induced Oncogenesis by Activation of Human PDGFRalpha;457
22.6.1;19.6.1 PDGFRalpha and HMCV IE1 Co-localize in Primary Human GBM Tissues and Cells;457
22.6.2;19.6.2 HCMV Promotes Glioma Cell Invasiveness by Engaging PDGFRalpha and the alphavbeta3 Integrin;458
22.6.3;19.6.3 Mechanisms of HCMV-Induced Oncogenesis in Human Adult Neural Precursor Cells;458
22.7;19.7 HCMV Association with Glioblastoma: Implications for Cancer Prevention, Detection, and Therapy;460
22.7.1;19.7.1 HCMV Association with Glioblastoma: Cause or Consequence?;460
22.7.2;19.7.2 Clinical Impact of HCMV Association with Glioblastoma: Implications for Cancer Prevention, Detection, Screening, and Treatment;461
22.8;19.8 Summary;461
22.9;References;463
23;Aberrant EGFR Signaling in Glioma;468
23.1;20.1 DeltaEGFR;468
23.2;20.2 Other Glioma-Associated Mutations of the EGFR;472
23.3;20.3 Clinical Significance of EGFR Abnormalities: Biomarker and Target;473
23.4;20.4 EGFR Localization Beyond the Plasma Membrane;476
23.5;References;480
24;Mechanisms of Brain Tumor Angiogenesis;487
24.1;21.1 Angiogenesis in Brain Tumors;488
24.1.1;21.1.1 Neovascularization as an Independent Prognostic Marker for Brain Tumors;489
24.1.2;21.1.2 How Angiogenesis Occurs in Brain Tumors;490
24.1.3;21.1.3 Morphology of Neo-Vessels and Blood-Brain Barrier (BBB) in Gliomas;491
24.2;21.2 Regulation in Brain Tumor Angiogenesis;491
24.2.1;21.2.1 VEGF-A and Its Isoforms;493
24.2.2;21.2.2 Other VEGF Family Members;494
24.2.3;21.2.3 VEGF Receptors (VEGFR);496
24.2.4;21.2.4 VEGFR-Mediated Signaling;497
24.2.5;21.2.5 Angiopoietins;501
24.2.6;21.2.6 Tie2-Mediated Signaling;503
24.2.7;21.2.7 Interaction Between Angiopoietins and Integrins;504
24.2.8;21.2.8 PDGF and Their Receptors;505
24.2.9;21.2.9 Other Growth Factors and Their Receptors: HGF/c-Met;506
24.2.10;21.2.10 FGF/FGFR;506
24.2.11;21.2.11 TGF-beta;507
24.2.12;21.2.12 Integrins;507
24.2.13;21.2.13 Interleukin-8 (IL-8);508
24.2.14;21.2.14 Nitric Oxide (NO);508
24.2.15;21.2.15 Hypoxia in Brain Tumor Angiogenesis;509
24.2.16;21.2.16 Hypoxia-Inducible Factor-1 (HIF-1);509
24.2.17;21.2.17 Induction of Angiogenic Inhibitors by Tumor Suppressor Genes;511
24.2.18;21.2.18 Contribution of Tumor Angiogenesis by Stem Cell-Like Glioma Cells;511
24.2.19;21.2.19 Anti-angiogenic Therapy of Brain Tumors: Clinical Applications and Challenges;512
24.3;21.3 Summary;513
24.4;References;513
25;Vaso-occlusive Mechanisms that Intiate Hypoxia and Necrosis in Glioblastoma: The Role of Thrombosis and Tissue Factor;533
25.1;22.1 Introduction;534
25.2;22.2 Distinctive Features of Glioblastoma;534
25.3;22.3 The Significance of Pseudopalisades, Necrosis, and Hypoxia;538
25.4;22.4 Vascular Pathology Underlies Hypoxia, Necrosis, and Pseudopalisades;539
25.5;22.5 Initiators of Vascular Pathology;540
25.6;22.6 Intravascular Thrombosis Accentuates and Propagates Tumor Hypoxia;540
25.7;22.7 Tissue Factor, a Potent Pro-Coagulant, Is Upregulated in GBM;541
25.8;22.8 PTEN, EGFR, and Hypoxia Regulate Tissue Factor Expression in GBM;542
25.9;22.9 TF Intitiates Signaling Through Its Cytoplasmic Tail and Through PARs;546
25.10;22.10 Angiogenesis Supports Peripheral Tumor Growth;547
25.11;22.11 Conclusion;549
25.12;References;549
26;Transcription Profiling of Brain Tumors: Tumor Biology and Treatment Stratification;555
26.1;23.1 Microarray Profiling;556
26.2;23.2 Expression Profiling in Human Brain Tumors;559
26.3;23.3 Expression Profiling of Human Gliomas;561
26.4;23.4 Molecular Subtypes of Infiltrating Gliomas;565
26.5;23.5 Stem-Cell Biomarkers;566
26.6;23.6 The Future of Profiling: Multiplatform Integration;567
26.7;23.7 Conclusions;568
26.8;References;568
27;Proteomic Profiling of Human Brain Tumors;578
27.1;24.1 Background;579
27.2;24.2 Protein Separation;580
27.2.1;24.2.1 Two-Dimensional Polyacrylamide Gel Electrophoresis (2D PAGE);580
27.2.2;24.2.2 Two-Dimensional Difference Gel Electrophoresis (2D DIGE);582
27.2.3;24.2.3 Liquid Chromatography (LC);583
27.3;24.3 MS-Based Protein Identification;584
27.3.1;24.3.1 Matrix-Assisted Laser Desorption/Ionization Time-of-Flight Mass Spectrometry (MALDI-TOF-MS);585
27.3.2;24.3.2 Surface-Enhanced Laser Desorption/Ionization Time-of-Flight Mass Spectrometry (SELDI-TOF-MS);586
27.4;24.4 Tissue Microarray (TMA);588
27.5;24.5 Protein and Antibody Array Analysis;589
27.6;24.6 Conclusion;593
27.7;References;596
28;Proteomic Discovery of Biomarkers in the Cerebrospinal Fluid of Brain Tumor Patients;601
28.1;25.1 Introduction;602
28.2;25.2 Why Proteomics?;602
28.3;25.3 Cerebrospinal Fluid as a Biomarker Repository;603
28.3.1;25.3.1 Composition of the CSF;603
28.3.2;25.3.2 Significance of CNS Barriers;606
28.4;25.4 CSF Proteomics for the Identification of CNS Neoplasia;608
28.4.1;25.4.1 The Promise of CSF Proteomics: The Identification of Markers of CNS Neoplasia for Patient Diagnosis, Prognosis, and Follow-Up After Therapy;608
28.4.2;25.4.2 Proteomic Methods for CSF Profiling;609
28.4.2.1;25.4.2.1 1-D and 2-D Gel Electrophoresis;611
28.4.2.2;25.4.2.2 Preparative 2-D Liquid-Phase Electrophoresis;613
28.4.2.3;25.4.2.3 MS Identification of 2-DE-Separated Proteins;613
28.4.3;25.4.3 Quantitative Proteomics;614
28.4.4;25.4.4 Initial Results and First Biomarker Panel for Brain Tumor CSF;615
28.4.5;25.4.5 Lessons Learned from Initial CSF Proteomic Studies;618
28.5;25.5 Importance of Experimental Design in CSF Proteomics;619
28.5.1;25.5.1 Accounting for Individual Variation Through Appropriate Biostatistical Design;619
28.5.2;25.5.2 Sample Selection and Processing;620
28.5.2.1;25.5.2.1 Prefractionation and Depletion of CSF;622
28.5.2.2;25.5.2.2 Preparation of CSF Samples;622
28.6;25.6 Data Analysis and Validation;623
28.7;25.7 Future Directions;624
28.7.1;25.7.1 Glyco-/Phospho Proteomics;624
28.7.2;25.7.2 Protein and Peptide Arrays;625
28.7.3;25.7.3 Antibody Arrays;625
28.7.4;25.7.4 Biomarker Panel;626
28.8;25.8 Conclusion;626
28.9;References;634
29;Epigenetic Profiling of Gliomas;638
29.1;26.1 A Central Role for Epigenetics in Biology;639
29.1.1;26.1.1 DNA Methylation and DNA Methyltransferases;639
29.1.2;26.1.2 Histone Modifications;640
29.1.3;26.1.3 Other Potential Epigenetic Factors;641
29.1.4;26.1.4 Epigenetic Regulation of Promoter CpG Islands;642
29.1.5;26.1.5 Functions of DNA Methylation;643
29.1.6;26.1.6 Environment and Epigenetics;644
29.1.7;26.1.7 Epigenetic Regulation in the CNS;645
29.1.8;26.1.8 Role of DNA Methyltransferases in the CNS;645
29.2;26.2 Epigenetic Dysregulation in Cancer;646
29.2.1;26.2.1 DNA Hypomethylation in Cancer;646
29.2.2;26.2.2 DNA Hypermethylation in Cancer;647
29.2.3;26.2.3 Histone Code Modifications and Cancer;648
29.2.4;26.2.4 Nucleosome Positioning Alterations in Cancer;649
29.2.5;26.2.5 Causes of Epigenetic Modifications in Cancer;649
29.2.6;26.2.6 Environmental Factors Affecting Epigenetic Modifications in Cancer;650
29.3;26.3 Epigenetic Dysregulation in Gliomas;651
29.3.1;26.3.1 Overview of Epigenetic Alterations in Gliomas;651
29.3.2;26.3.2 Epigenetic Silencing of MGMT and Drug Resistance to Alkylating Agents;652
29.3.3;26.3.3 Patterns of Epigenetic Alterations in Gliomas;653
29.3.4;26.3.4 Epigenetics of Glioma Tumor Initiating Cells;654
29.3.5;26.3.5 Identification of Genome-Wide Methylation Patterns in Brain Tumors;655
29.3.6;26.3.6 Aberrant Expression of MicroRNAs in Gliomas;656
29.4;26.4 Targeting Epigenetic Events for Therapy in Gliomas;656
29.4.1;26.4.1 Overview of Epigenetic Therapy for Gliomas;656
29.4.2;26.4.2 Histone Deacetylase (HDAC) Inhibitors for Glioma Treatment;657
29.4.3;26.4.3 Epigenetic Marks as Biomarkers for Clinical Evaluation;659
29.5;26.5 Future Directions for Epigenetics of Gliomas;660
29.6;References;661
30;MicroRNAs in the Central Nervous System and Potential Roles of RNA Interference in Brain Tumors;674
30.1;27.1 Introduction;675
30.2;27.2 miRNA and siRNA Background;675
30.3;27.3 MicroRNAs in CNS Development and Function;678
30.4;27.4 Individual MicroRNAs in the CNS;679
30.5;27.5 MicroRNAs in Cancer;680
30.6;27.6 MicroRNAs in Brain Tumors;683
30.6.1;27.6.1 Oncogenic miRNAs in Brain Tumors;684
30.6.2;27.6.2 miRNAs with Tumor Suppressor Properties in Brain Tumors;686
30.7;27.7 Potential miRNA- and siRNA-Based Therapies for Brain Tumors;687
30.7.1;27.7.1 Delivery of siRNAs or miRNAs as Therapy;687
30.7.2;27.7.2 Oncogenic miRNA-Based Therapies;688
30.7.3;27.7.3 Tumor-Suppressive miRNA-Based Therapies;688
30.7.4;27.7.4 Indirect miRNA-Based Strategies for Brain Tumor Therapy;689
30.8;27.8 Conclusion;690
30.9;References;691
31;Of Escherichia coli and Man: Understanding Glioma Resistance to Temozolomide Therapy;701
31.1;28.1 Introduction;702
31.2;28.2 Temozolomide (TMZ): Chemical Properties;703
31.3;28.3 Repair of Temozolomide-Induced DNA Damage in E. coli;703
31.3.1;28.3.1 N7-Methyl Guanine;703
31.3.2;28.3.2 N3-Methyl Adenine;705
31.3.3;28.3.3 N3-Methyl Cytosine;708
31.3.4;28.3.4 O6-Methyl Guanine;708
31.4;28.4 Evolutionarily Conserved Temozolomide Resistance Mechanisms;712
31.4.1;28.4.1 N7-Methyl Guanine;713
31.4.2;28.4.2 N3-Methyl Adenine;714
31.4.3;28.4.3 N3-Methyl Cytosine;714
31.4.4;28.4.4 O6-Methyl Guanine;715
31.4.5;28.4.5 MMR and DNA Damage Checkpoint Activation;717
31.4.6;28.4.6 Fanconi Anemia (FA) DNA Repair Pathway;719
31.5;28.5 Temozolomide Resistance Mechanism Unique to Higher Eukaryotes;721
31.5.1;28.5.1 p53;721
31.5.2;28.5.2 Autophagy;722
31.6;28.6 Conclusion;723
31.7;References;725
32;Brain Tumor Stem Cell Markers;734
32.1;29.1 Introduction;735
32.2;29.2 Tumor Stem Cell Markers;736
32.3;29.3 Prominin-1/CD133;738
32.4;29.4 Nestin;740
32.5;29.5 Bmi1;740
32.6;29.6 Musashi1;741
32.7;29.7 Notch;741
32.8;29.8 Sox2;741
32.9;29.9 A2B5;742
32.10;29.10 Other Potential Brain Tumor Stem Cell Markers;742
32.11;29.11 Perspectives;742
32.12;29.12 Conclusions;743
32.13;References;743
33;Part 3: Therapeutic Targets and Targeting Approaches;750
34;Clinical Agents for the Targeting of Brain Tumor Vasculature;751
34.1;30.1 Introduction;752
34.2;30.2 Angiogenesis in Gliomas;752
34.3;30.3 Antibodies to Growth Factors/Receptors;755
34.3.1;30.3.1 Bevacizumab (Avastin);756
34.3.2;30.3.2 Aflibercept (VEGF-Trap);757
34.4;30.4 Tyrosine Kinase Inhibitors;757
34.4.1;30.4.1 Cediranib (Recentin);757
34.4.2;30.4.2 Vatalanib;758
34.4.3;30.4.3 Other TKIs;758
34.5;30.5 Resistance to Anti-VEGF Therapy;759
34.6;30.6 Toxicities of Anti-VEGF Agents;759
34.7;30.7 VEGF-Inhibitors as Anti-edema Therapies;760
34.8;30.8 Assessing Glioblastoma Response and Progression with Anti-VEGF Therapies;761
34.9;30.9 Future Role of Anti-VEGF Agents in the Therapy of Glioblastoma;762
34.10;References;763
35;Bone Marrow-Derived Cells in GBM Neovascularization;768
35.1;31.1 Introduction;769
35.1.1;31.1.1 Neovascularization Is a Prerequisite for Tumor Progression;769
35.1.2;31.1.2 Tumor Neovascularization Is Driven by Angiogenic and Vasculogenic Mechanisms;770
35.2;31.2 Bone Marrow-Derived Cells Contribute to Neovascularization in GBM;771
35.2.1;31.2.1 Vascular Progenitor Cells;773
35.2.1.1;31.2.1.1 Endothelial Progenitor Cells (EPC);774
35.2.1.2;31.2.1.2 Pericyte Progenitor Cells (PPC);778
35.2.2;31.2.2 Proangiogenic Myeloid Support Cells;779
35.2.2.1;31.2.2.1 Tumor-Associated Macrophages (TAM);780
35.2.2.2;31.2.2.2 TIE2-Expressing Monocytes (TEM);782
35.2.2.3;31.2.2.3 VEGFR1+ CXCR4+ Hemangiocytes;783
35.2.2.4;31.2.2.4 Myeloid-Derived Suppressor Cells (MDSC);783
35.3;31.3 Conclusions;784
35.4;References;787
36;Vascular Targeting of Brain Tumors - Bridging the Gap with Phage Display;793
36.1;32.1 Introduction;794
36.2;32.2 The Principles of Phage Display;795
36.3;32.3 The Blood-Brain Barrier;797
36.4;32.4 Glioblastoma and Angiogenesis;798
36.5;32.5 Targeting of the Brain Tumors by Phage Display;799
36.6;32.6 Targeted Therapy and Imaging;800
36.6.1;32.6.1 AAVP, a Novel Hybrid Gene Delivery System;801
36.7;32.7 Conclusions;802
36.8;References;803
37;Impact of the Blood-Brain Barrier on Brain Tumor Imaging and Therapy;806
37.1;33.1 Introduction;807
37.2;33.2 Historical Beginnings of the BBB Concept;807
37.3;33.3 Structure and Function of the Blood-Brain Barrier;808
37.3.1;33.3.1 Renewed Emphasis on Understanding of the Blood-Brain Barrier;811
37.4;33.4 Importance of the BBB for Imaging of Brain Tumors;814
37.4.1;33.4.1 Angiogenesis and Permeability: Similarities and Differences;814
37.4.2;33.4.2 Permeability as a Surrogate Marker for Angiogenesis;814
37.4.3;33.4.3 T1-Weighted Imaging Techniques;815
37.4.4;33.4.4 Dynamic Susceptibility Contrast MR Imaging in Brain Tumor Assessment;818
37.4.5;33.4.5 Correlation of MR Perfusion Imaging with Angiographic and Histological Tumor Features;819
37.5;33.5 Importance of BBB for Therapy of Brain Tumors;820
37.5.1;33.5.1 Impact on Brain Tumor Therapy;820
37.5.2;33.5.2 Enhanced Transit of Agents across the Blood-Brain Barrier;821
37.5.3;33.5.3 Drug Dose Intensification;821
37.5.4;33.5.4 BBB Alteration to Allow Increased Drug Transport;821
37.5.5;33.5.5 Drugs with Increased Transport Capabilities Across the BBB;822
37.5.6;33.5.6 Local Delivery Techniques;823
37.5.7;33.5.7 Convection-Enhanced Delivery;823
37.5.8;33.5.8 Assessment of Drug Pharmacokinetics Within Brain Tissue;823
37.6;33.6 Summary;824
37.7;References;825
38;Targeting CXCR4 in Brain Tumors;829
38.1;34.1 Introduction;830
38.2;34.2 Classification of Chemokines and Their Receptors;831
38.3;34.3 History of CXCR4/CXCL12;833
38.4;34.4 Functions of CXCR4 in the Normal CNS;834
38.5;34.5 Involvement of CXCR4 in Non-CNS Cancers;836
38.6;34.6 Involvement of CXCR4 in Glioma;842
38.7;34.7 Involvement of CXCR4 in Medulloblastoma;843
38.8;34.8 Involvement of CXCR4 in Meningioma;844
38.9;34.9 Involvement of CXCR4 in Neuroblastoma;845
38.10;34.10 Concluding Remarks;846
38.11;References;847
39;Molecular Targeting of IL-13Ralpha2 and EphA2 Receptor in GBM;862
39.1;35.1 Molecularly Targeted Recombinant Cytotoxins for the Treatment of Brain Tumors;863
39.2;35.2 Targetable Molecular Fingerprints in GBM;865
39.2.1;35.2.1 Overexpression of IL-13Ralpha2 in GBM;865
39.2.2;35.2.2 Targeting IL-13Ralpha2 for Therapeutic Purposes;867
39.2.3;35.2.3 EphA2 Receptor in GBM;869
39.2.3.1;35.2.3.1 EphA2 Protein Expression in GBM Cells and Tumors;870
39.2.3.2;35.2.3.2 Function of EphA2 in GBM;872
39.2.3.3;35.2.3.3 Targeting EphA2 in GBM with EphrinA1-Based Cytotoxins;872
39.3;35.3 Summary;874
39.4;References;874
40;Molecular Targets for Antibody-Mediated Immunotherapy of Malignant Glioma;879
40.1;36.1 Introduction;879
40.2;36.2 Brain-Tumor Targets and Immunotherapeutic Antibodies;883
40.2.1;36.2.1 Tenascin;883
40.2.2;36.2.2 Epidermal Growth Factor Receptor and Its Variant III Form;890
40.2.3;36.2.3 Chondroitin Sulfate Proteoglycans;893
40.2.4;36.2.4 Other Molecular Targets of Interest;895
40.2.4.1;36.2.4.1 Gangliosides;895
40.2.4.2;36.2.4.2 Glycoprotein Nonmetastatic Melanoma Protein B;895
40.2.4.3;36.2.4.3 Multidrug Resistance Protein 3;897
40.2.4.4;36.2.4.4 Podoplanin;897
40.2.4.5;36.2.4.5 Neural Cell Adhesion Molecule;898
40.2.4.6;36.2.4.6 Vascular Endothelial Growth Factor;899
40.3;36.3 Perspective;899
40.4;36.4 Conclusion;901
40.5;References;902
41;Stat3 Oncogenic Signaling in Glioblastoma Multiforme;913
41.1;37.1 Introduction;914
41.2;37.2 Biology of Malignant Gliomas;915
41.3;37.3 Activated Stat3 Acts as an Oncoprotein;917
41.4;37.4 Stat3 Signaling Is Activated in GBM and Other Brain Tumors;917
41.5;37.5 Activated Stat3 Induces Proliferation and Survival of GBM Cells;918
41.6;37.6 Proangiogenic Activity of Stat3 in GBM;920
41.7;37.7 Immune Suppression by Stat3 in GBM;921
41.8;37.8 Antitumor Activity of Stat3 in GBM;922
41.9;37.9 Physiologic and Pharmacologic Inhibitors of Stat3;923
41.10;37.10 Perspectives;925
41.11;References;925
42;Inhibition of Ras Signaling for Brain Tumor Therapy;933
42.1;38.1 Introduction;934
42.2;38.2 p21-Ras Structure and Processing;934
42.3;38.3 Activation and p21-Ras Signaling;937
42.4;38.4 Mutated and Activated p21-Ras in Brain Tumors;938
42.5;38.5 Farnesyltransferase Inhibitors (FTIs) and Preclinical Studies;939
42.6;38.6 Alternative Methods to Target p21-Ras Signaling;941
42.7;38.7 p21-Ras Signaling in Non-glioma CNS Tumors;942
42.8;38.8 Conclusion;942
42.9;References;943
43;HGF/c-Met Signaling and Targeted Therapeutics in Brain Tumors;947
43.1;39.1 Introduction;948
43.2;39.2 c-Met and HGF Structure and Signal Transduction;948
43.2.1;39.2.1 Structure of HGF and c-Met;948
43.2.2;39.2.2 c-Met-Dependent Signal Transduction;949
43.3;39.3 Involvement of HGF/c-Met in Brain Tumors;951
43.3.1;39.3.1 Deregulation of HGF and c-Met in Brain Tumors;951
43.3.1.1;39.3.1.1 Mechanisms of HGF and c-Met Deregulation in Brain Tumors;951
43.3.1.2;39.3.1.2 HGF and c-Met Expression in Brain Tumors;952
43.3.1.3;39.3.1.3 HGF and c-Met Expression in Brain Tumor Endothelial Cells;953
43.3.2;39.3.2 Oncogenic Effects of c-Met Activation in Brain Tumors;953
43.3.2.1;39.3.2.1 Cell Proliferation;953
43.3.2.2;39.3.2.2 Cell Survival;954
43.3.2.3;39.3.2.3 Cell Migration and Cell Invasion;955
43.3.2.4;39.3.2.4 Angiogenesis;955
43.4;39.4 HGF and c-Met as Targets for Brain Tumor Therapy;956
43.4.1;39.4.1 U1snRNA/Ribozymes and Antisense;957
43.4.2;39.4.2 NK4;958
43.4.3;39.4.3 Soluble Met;959
43.4.4;39.4.4 Small-Molecule Inhibitors;959
43.4.5;39.4.5 Neutralizing Monoclonal Antibodies;960
43.5;39.5 Therapeutic Considerations;962
43.6;References;962
44;Combinatorial Therapeutic Strategies for Blocking Kinase Pathways in Brain Tumors;967
44.1;40.1 Introduction: From Single Genes to Biological Networks;968
44.2;40.2 Robustness in Oncogenic Signaling Networks;968
44.2.1;40.2.1 The Akt-mTOR Feedback Loop;969
44.2.2;40.2.2 EGFRvIII-PTEN Connection;971
44.2.3;40.2.3 The RAS-PI3K Crosstalk;972
44.3;40.3 Tools to Survey Signaling Networks in GBM;973
44.3.1;40.3.1 Revealing Novel Network Connections Through Mass Spectrometry;973
44.3.2;40.3.2 Understanding Chemoresistance Through the Use of Antibody Microarrays;975
44.3.3;40.3.3 Multiparameter Flow Cytometry as a Tool for Determining Oncogenic Networks in Cancer Stem Cell Populations;976
44.4;40.4 Combinatorial Targets from GBM Signaling Networks Through Integrative Analysis;977
44.5;40.5 Mechanistic Models and Computational Approaches to Drug Targets;980
44.6;40.6 Bench to Bedside - Can Integrative Strategies Be Extended to the Clinic?;981
44.7;40.7 Conclusions;983
44.8;References;984
45;Targeting of TRAIL Apoptotic Pathways for Glioblastoma Therapies;990
45.1;41.1 Introduction;991
45.2;41.2 Development of TNF Family Death Receptors Targeted Cancer Therapies;992
45.2.1;41.2.1 Toxicity in TNFR and Fas-Targeted Therapies;992
45.2.2;41.2.2 Controversy in TRAIL-Induced Toxicity;993
45.3;41.3 TRAIL-Induced Apoptotic Pathways in Human Cancer Cells;994
45.3.1;41.3.1 TRAIL-Induced DISC and Extrinsic Apoptotic Pathway;994
45.3.2;41.3.2 TRAIL-Induced Intrinsic Apoptotic Pathway;995
45.3.3;41.3.3 Caspase-8 in TRAIL-Induced Apoptosis;996
45.3.4;41.3.4 TRAIL-Induced Apoptosis in Glioblastoma Cells;996
45.4;41.4 TRAIL Resistance in Human Cancers;997
45.4.1;41.4.1 Decoy Receptors;997
45.4.2;41.4.2 DISC Modifications;998
45.4.3;41.4.3 NF-kappaB and ERK1/2 Pathways;999
45.4.4;41.4.4 Bcl-2 and IAP Family Proteins;1000
45.4.5;41.4.5 Cancer Genomics;1000
45.4.6;41.4.6 TRAIL Resistance in Glioblastomas;1001
45.5;41.5 Development of TRAIL-Based Combination Therapies;1002
45.5.1;41.5.1 Targeting of TRAIL Resistance in the DISC and Mitochondrial Pathway;1002
45.5.2;41.5.2 Targeting Oncogene-Driven Signaling Pathways;1003
45.5.3;41.5.3 Combination of TRAIL and Chemotherapy;1003
45.5.4;41.5.4 TRAIL-Based Combination Therapies for Glioblastomas;1004
45.6;41.6 Clinical Development of TRAIL Agonists for Cancer Therapies;1005
45.6.1;41.6.1 Clinical Trials of rhTRAIL;1005
45.6.2;41.6.2 Clinical Trials of DR4 and DR5 Agonistic Antibodies;1006
45.7;41.7 Development of TRAIL-Based Treatments of Glioblastomas;1007
45.7.1;41.7.1 TRAIL-Based Therapeutic Modalities;1008
45.7.2;41.7.2 Evaluation of Patient Glioblastomas in TRAIL-Based Treatments;1009
45.8;41.8 Conclusions and Future Directions;1009
45.9;References;1010
46;The NF-kappaB Signaling Pathway in GBMs: Implications for Apoptotic and Inflammatory Responses and Exploitation for Therapy;1023
46.1;42.1 NF-kappaB Family and Signaling Pathway;1024
46.2;42.2 NF-kappaB and Angiogenesis;1027
46.3;42.3 NF-kappaB and Cell Migration and Invasion;1028
46.4;42.4 NF-kappaB and Cellular Proliferation;1028
46.4.1;42.4.1 Cyclin D1, E, and CDK2;1028
46.4.2;42.4.2 c-Myc;1029
46.4.3;42.4.3 Interleukin-6;1029
46.5;42.5 NF-kappaB and Apoptosis;1030
46.6;42.6 Activation of NF-kappaB in Gliomas;1033
46.6.1;42.6.1 Immune Cell Infiltration;1033
46.6.2;42.6.2 The PI3K Pathway;1034
46.6.3;42.6.3 ING4;1034
46.6.4;42.6.4 Pin1;1035
46.6.5;42.6.5 PIAS Family;1036
46.6.6;42.6.6 Alternative Reading Frame (ARF);1036
46.6.7;42.6.7 DNA Damage and Reactive Oxygen Species (ROS);1036
46.7;42.7 Targeting NF-kappaB in Gliomas;1037
46.7.1;42.7.1 Proteasome Inhibitors;1038
46.7.2;42.7.2 IKK Inhibitors;1039
46.7.3;42.7.3 Antioxidants;1040
46.8;42.8 Conclusions;1041
46.9;References;1041
47;Targeting Endoplasmic Reticulum Stress for Malignant Glioma Therapy;1049
47.1;43.1 Introduction;1050
47.2;43.2 ER Stress Response (ESR);1050
47.3;43.3 Downregulation of the ER Chaperone GRP78 Results in Increased Glioma Cell Sensitivity to Temozolomide (TMZ);1053
47.4;43.4 ER Stress Modulation of Intracellular Calcium in Malignant Gliomas;1055
47.5;43.5 Induction of ER Stress by Affecting Protein Balance in the ER;1058
47.6;43.6 Combination Therapy by Affecting Multiple Targets Within the ER;1060
47.7;43.7 Potential Clinical Applications of ER Stress Modulation in Malignant Glioma Treatment;1061
47.8;43.8 Conclusion;1064
47.9;References;1064
48;Brain Cancer Stem Cells as Targets of Novel Therapies;1069
48.1;44.1 Introduction;1070
48.2;44.2 Defining Cancer Stem Cells;1070
48.3;44.3 Signaling Pathways as Drug Targets in Cancer Stem Cells;1071
48.3.1;44.3.1 Epidermal Growth Factor and PI(3)K Signaling;1072
48.3.2;44.3.2 Hedgehog Signaling;1073
48.3.3;44.3.3 Bone Morphogenic Protein Signaling;1074
48.3.4;44.3.4 Notch Signaling;1074
48.3.5;44.3.5 Platelet-Derived Growth Factor Signaling;1074
48.3.6;44.3.6 Additional CSC Regulators;1074
48.4;44.4 Targeting the Perivascular Stem Cell Niche;1075
48.5;44.5 Cancer Stem Cells and Niches in Therapeutic Resistance;1077
48.5.1;44.5.1 Cancer Stem Cells Are Resistant to Conventional Therapy;1077
48.5.2;44.5.2 Cancer Stem Cells Express High Levels of ABC Drug Transporters;1077
48.5.3;44.5.3 Cancer Stem Cells Have Augmented DNA Damage Repair Capacity;1078
48.5.4;44.5.4 The Perivascular Niche Contributes to Cancer Stem Cell Resistance to Therapy;1078
48.6;44.6 Cancer Stem Cells as Markers of Prognosis;1079
48.7;44.7 Imaging of Cancer Stem Cells;1079
48.8;44.8 Perspectives;1080
48.9;44.9 Summary;1081
48.10;References;1081
49;The Use of Retinoids as Differentiation Agents Against Medulloblastoma;1088
49.1;45.1 Introduction-Medulloblastoma (MB) as a Lapse of Proper Development;1089
49.1.1;45.1.1 Normal Cerebellum Development;1090
49.1.2;45.1.2 Mice with Dysregulated Shh Signaling Develop Desmoplastic/Nodular MB;1091
49.1.3;45.1.3 Wnt Pathway Activation in Classic MBs;1091
49.1.4;45.1.4 Notch Amplification and Overexpression in MBs;1092
49.1.5;45.1.5 OTX2 Amplification and Overexpression in Anaplastic MBs;1092
49.2;45.2 Endogenous Retinoid Function;1093
49.2.1;45.2.1 An Introduction to Retinoid Metabolism and Signal Regulation;1093
49.2.2;45.2.2 Retinoids Function by Activating Ligand-Activated Transcription Factors;1093
49.2.3;45.2.3 Endogenous Function of Retinoids During Embryonic Development;1094
49.2.4;45.2.4 A Focus upon ATRA Function in Cerebellar Development;1095
49.3;45.3 Therapeutic Application of Retinoids;1096
49.3.1;45.3.1 A Link Between Vitamin A Deficiency and Cancer;1096
49.3.2;45.3.2 Clinical Application of Retinoids;1097
49.3.3;45.3.3 Mechanisms of Retinoid Antitumor Activity;1098
49.3.4;45.3.4 Retinoid Therapy Targets Pathways Implicated in MB Tumorigenesis;1099
49.3.4.1;45.3.4.1 Variability of Retinoid Responsiveness Among MB Cell Lines Resulted in Disproportionately Negative Results in Early Studies;1101
49.3.4.2;45.3.4.2 ATRA Can Induce Reversible Differentiation and Chemosensitize MB Cells;1101
49.3.4.3;45.3.4.3 ATRA Can Introduce a Cell Cycle Blockade in an MB Cell Line;1102
49.3.4.4;45.3.4.4 Identifying a Predominantly Apoptotic Response to ATRA in Some MB Cell Lines;1102
49.3.4.5;45.3.4.5 Bmp2 Is a Functional Downstream Target of Retinoid Treatment in MB Cell Lines and Surgically Derived Primary Tumors;1103
49.3.4.6;45.3.4.6 ATRA Treatment Silences the Oncogene OTX2, Which Is Distinctly Expressed in Retinoid-Sensitive Cell Lines;1104
49.3.4.7;45.3.4.7 Development of Retinoid-Based Therapeutic Strategies in Preclinical Models;1105
49.3.4.8;45.3.4.8 A Synthetic Retinoid, Fenretinide, Induces Apoptosis in MBs via an RAR-Independent Effect;1106
49.3.4.9;45.3.4.9 Overview of Known Retinoid Targets in MB;1106
49.3.4.10;45.3.4.10 Strategies to Identify Mechanisms of Retinoid Resistance in MB Cell Lines;1107
49.3.4.11;45.3.4.11 Clinical Trials Utilizing Retinoid Treatment for MB;1108
49.4;45.4 Overview of Retinoid-Mediated Differentiation Therapy of MB;1108
49.5;References;1109
50;Herpes Simplex Virus 1 (HSV-1) for Glioblastoma Multiforme Therapy;1116
50.1;46.1 Introduction;1117
50.2;46.2 Basic Biology of HSV-1;1118
50.2.1;46.2.1 HSV-1 Structure and Genome;1118
50.2.2;46.2.2 HSV-1 Cell Entry;1119
50.2.3;46.2.3 HSV-1 Pathogenesis;1121
50.2.4;46.2.4 HSV-1 Gene Expression;1121
50.2.5;46.2.5 HSV-1 Latency;1122
50.2.6;46.2.6 HSV-1 Immediate-Early (IE) Proteins;1123
50.2.7;46.2.7 HSV-1 DNA Replication and Recombination;1124
50.2.8;46.2.8 HSV-1 Assembly and Release;1124
50.3;46.3 HSV-1 as a Gene Therapy Vector Against Malignant Gliomas;1125
50.3.1;46.3.1 HSV-1 Replication-Defective Mutants;1125
50.3.1.1;46.3.1.1 Generation of Replication-Deficient HSV-1 Viruses;1125
50.3.1.2;46.3.1.2 Replication-Defective HSV-1 in Malignant Glioma Therapy;1126
50.3.2;46.3.2 HSV-1 Replication-Conditional (Oncolytic) Viruses;1127
50.4;46.4 Combination Therapies with HSV-1 for Malignant Gliomas;1128
50.4.1;46.4.1 HSV-1 d106-Mediated Chemoradiosensitivity Enhancement in GBM;1129
50.4.1.1;46.4.1.1 ICP0 and Effects on Cell Metabolism;1130
50.5;46.5 Clinical Trials with HSV-1 Based Viruses for Malignant Glioma Therapy;1131
50.6;46.6 Limitations in the Treatment of Malignant Gliomas with HSV-Mediated Therapy;1133
50.6.1;46.6.1 Delivery;1133
50.6.2;46.6.2 Host Immune Response;1134
50.6.3;46.6.3 Safety;1134
50.7;46.7 Perspectives;1135
50.7.1;46.7.1 Tumor Targeting of HSV-1;1135
50.7.2;46.7.2 Chemo/Radiotherapy-Activated Transcriptional Targeting of Malignant Gliomas;1136
50.7.3;46.7.3 Imaging;1136
50.8;46.8 Summary;1136
50.9;References;1137
51;The Development of Targeted Cancer Gene-Therapy Adenoviruses for High-Grade Glioma Treatment;1148
51.1;47.1 Historic Background;1149
51.2;47.2 The Ad as a Cancer Therapy Agent;1149
51.2.1;47.2.1 Replication-Deficient Ads;1150
51.2.2;47.2.2 Tumor-Specific Replication-Competent Ads;1151
51.2.3;47.2.3 Advantages and Disadvantages of Using the Ad as a Cancer Therapy Agent;1154
51.3;47.3 Clinical Trials of Cancer Therapy Ads for Glioma Therapy;1155
51.3.1;47.3.1 Ad-HSV-TK Clinical Trials;1155
51.3.2;47.3.2 Ad-p53 Clinical Trial;1159
51.3.3;47.3.3 Ad-IFNbeta Clinical Trial;1159
51.3.4;47.3.4 E1B-55K-Deleted Oncolytic Ad (dl1520, ONYX-015) Clinical Trial;1160
51.3.5;47.3.5 Clinical Trial Data: Anti-Ad Neutralizing Antibody Levels;1160
51.3.6;47.3.6 Clinical Trial Data: Regional and Systemic Virus Dissemination;1161
51.3.7;47.3.7 Clinical Trial Data: Antitumor Efficacy;1161
51.4;47.4 Future Directions to Improve the Safety and Efficacy of Cancer Gene-Therapy and Oncolytic Ads for Glioma Therapy;1162
51.4.1;47.4.1 Preclinical Brain Tumor Models;1162
51.4.2;47.4.2 Improving the Virus Vectors;1164
51.4.3;47.4.3 Improving Virus Delivery, Intratumoral Dispersion, and Transduction of Tumor Cells;1165
51.4.4;47.4.4 Local and Systemic Host Immune Response;1166
51.4.5;47.4.5 Tracking Viral Replication in the Patient;1167
51.5;47.5 Summary;1168
51.6;References;1168
52;Harnessing T-Cell Immunity to Target Brain Tumors;1176
52.1;48.1 Introductory Remarks;1177
52.2;48.2 Immune Privilege and Cancer Immunosurveillance;1177
52.3;48.3 The Stages of Tumor Immunity;1178
52.3.1;48.3.1 The Tumor First Stimulates Innate Immune Sentinels, at the Site of the Malignancy;1179
52.3.1.1;48.3.1.1 Detection;1179
52.3.1.2;48.3.1.2 Innate Immune Functions;1180
52.3.2;48.3.2 The Induction of Adaptive Immune Responses Against Brain Tumors: From the Brain to the Lymph Node;1181
52.3.2.1;48.3.2.1 Generation of Naïve CD4 and CD8 T Cells;1181
52.3.2.2;48.3.2.2 Naïve T-Cell Activation Requires Two Signals;1182
52.3.2.3;48.3.2.3 How Does Antigen from the Tumor Site Reach the Naïve T Cells in the Lymph Node?;1183
52.3.2.4;48.3.2.4 Cell-Free Drainage of Antigen;1184
52.3.2.5;48.3.2.5 Cell-Mediated Transport of Antigen from the Brain to the Lymph Node;1184
52.3.3;48.3.3 The Effector Phase of the T-Cell Mediated Antitumor Response: From the Lymph Node to the Brain;1185
52.3.3.1;48.3.3.1 T-Cell Entry to the Brain and Antigen Specificity;1185
52.3.3.2;48.3.3.2 Antigen-Independent T-Cell Extravasation to the Brain;1186
52.3.3.3;48.3.3.3 Role of Integrins in CNS Tropism;1187
52.3.3.4;48.3.3.4 Role of Non-integrin Adhesion Molecules;1187
52.3.3.5;48.3.3.5 Role of Chemokines and Chemokine Receptors;1188
52.3.3.6;48.3.3.6 Suboptimal Trafficking of T Cells to Brain Tumors May Lead to Suboptimal Tumor Therapies;1189
52.3.4;48.3.4 The Effector Phase of the T-Cell Mediated Antitumor Response: At the Tumor Site;1190
52.3.4.1;48.3.4.1 CD8 T Cells;1190
52.3.4.2;48.3.4.2 CD4 T Cells;1191
52.4;48.4 Glioma Immune Escape;1191
52.4.1;48.4.1 Passive Immune Escape Mechanisms;1192
52.4.2;48.4.2 Active Immune Escape;1192
52.4.2.1;48.4.2.1 Soluble Immunosuppresive Molecules;1193
52.4.2.2;48.4.2.2 Cell Surface Immunosuppressive Factors;1193
52.4.2.3;48.4.2.3 Immunosuppressive Cells;1194
52.5;48.5 Identification of Glioma-Associated Antigens;1195
52.5.1;48.5.1 Identifying Tumor-Associated-Antigens (‘‘Reverse Immunology’’);1195
52.5.2;48.5.2 Microarray Technology and Tumor-Associated-Antigens;1196
52.6;48.6 Preclinical Studies of T-Cell Immunity to Target Brain Tumors;1197
52.6.1;48.6.1 Passive Immunotherapy;1197
52.6.1.1;48.6.1.1 Adoptive Transfer;1197
52.6.1.2;48.6.1.2 Cytokines;1198
52.6.1.3;48.6.1.3 Toll- Like Receptor Agonists;1198
52.6.2;48.6.2 Active Immunotherapy (Tumor Vaccines);1198
52.6.2.1;48.6.2.1 Dendritic Cell-Based Vaccines;1199
52.6.2.2;48.6.2.2 Adjuvants;1200
52.6.2.3;48.6.2.3 Blocking Regulatory T Cells (Tregs);1200
52.6.2.4;48.6.2.4 Immune Gene Therapy;1201
52.6.2.5;48.6.2.5 Bacterial/Viral-Based Vaccines;1201
52.7;48.7 Clinical Trials of Cellular Immunotherapy for Brain Tumors;1202
52.7.1;48.7.1 Lymphokine-Activated Killer Cells;1202
52.7.2;48.7.2 Cytotoxic T Lymphocytes;1202
52.7.3;48.7.3 Dendritic Cell Vaccination Trials;1203
52.7.4;48.7.4 Bacterial and Viral Tumor Vaccine Trials for Malignant Glioma;1207
52.8;48.8 Conclusion;1208
52.9;References;1215
53;Glioma Invasion: Mechanisms and Therapeutic Challenges;1229
53.1;49.1 Introduction;1230
53.2;49.2 Overview of Glioma Cell Invasion in the CNS;1230
53.3;49.3 Glioma Cell Microenvironment: Extracellular Matrix;1235
53.3.1;49.3.1 Neural ECM;1235
53.3.2;49.3.2 Basal Lamina;1239
53.4;49.4 Extracellular Remodeling and Glioma Invasion;1240
53.4.1;49.4.1 ECM Degradation;1240
53.4.2;49.4.2 ECM Synthesis;1244
53.5;49.5 Soluble Signals and Transduction Mechanisms in Glioma Invasion;1247
53.5.1;49.5.1 Chemoattractants;1247
53.5.2;49.5.2 Chemorepellents;1249
53.6;49.6 Targeting Strategies Against Glioma Cell Invasion;1250
53.7;References;1254
54;Index;1263