Preface 5
Contents 6
Contributors 8
Overview of the Molecular Genetics and Molecular Chemotherapy of GBM 11
Introduction 12
Growth Factor Signaling – PDGF and PDGFR 13
Growth Factor Signaling – EGF and EGFR 17
Ras Signaling 23
Raf/MEK Signaling 26
PI3K/Akt Signaling 28
mTOR Signaling 32
Angiogenesis and Vascular Endothelial Growth Factor 35
Multitargeted Molecular Chemotherapeutic Agents 40
Future Directions 41
References 42
Primary Brain Tumors: Characteristics, Practical Diagnostic and Treatment Approaches 53
Introduction 54
Neuroepithelial Tumors 55
Localized Gliomas: Pilocytic Astrocytoma and Subependymal Giant Cell Astrocytoma (WHO Grade I, Low Grade Astrocytoma) 55
Diffuse Gliomas: Diffuse Astrocytoma, Oligodendroglioma, Oligoastrocytoma (WHO Grade II, Low Grade), Anaplastic Astrocytoma, An 56
Diffuse Astrocytoma (WHO Grade II, Low-Grade Astrocytoma) 56
Oligodendroglioma and Oligoastrocytomas (Grade II, Low-Grade Oligodendroglial Tumors) 57
Treatment 59
Surgery 60
Radiation Therapy 61
Chemotherapy 63
Malignant Gliomas: Anaplastic Astrocytoma, Anaplastic Oligodendroglioma, Anaplastic Oligoastrocytoma (WHO Grade III, High Grade 64
Anaplastic Astrocytoma (Grade III Astrocytoma) and Glioblastoma Multiforme (Grade IV Astrocytoma) 65
Anaplastic Oligodendroglioma and Anaplastic Oligoastrocytoma (Grade III Oligodendroglioma and Grade III Oligoastrocytoma) 66
Treatment 67
Surgery 67
Radiation 67
Chemotherapy 67
Temozolomide 69
Nitrosoureas 70
BCNU (Carmustine) 70
CCNU (Lomustine) 71
Platinum Compounds 71
Carboplatin 71
PCV (Procarbazine, CCNU, Vincristine) 71
Tamoxifen 72
Molecular Targeted Therapy 72
Bevacizumab (Avastin) 72
Erlotinib (Tarceva) 73
Other Neuroepithelial Tumors 73
Ependymoma 73
Treatment 74
Non-neuroepithelial Tumors 75
Meningioma 75
Treatment 76
Surgery 76
Radiation 76
Chemotherapy/Immunotherapy 76
Recombinant Interferon (IFN-alpha-2b) 77
Hydroxyurea 77
Somatostatin 77
Primary Central Nervous System Lymphoma 77
Treatment 79
Surgery 79
Radiation 79
Chemotherapy 80
High-Dose Methotrexate 80
Rituximab 80
References 81
Pathology of Glioblastoma Multiforme 86
Introduction 86
General Features 87
Macroscopy 88
Microscopy 88
Immunohistochemistry 91
Differential Diagnosis 92
Prognostic Factors 93
References 93
Molecular Mechanisms of Pathogenesis in Glioblastoma and Current Therapeutic Strategies 94
Introduction 94
Grading 95
Stem Cells 96
Invasiveness 97
Glioblastoma 98
Genetics 98
Necrosis 99
Angiogenesis 99
Traditional and Innovative Therapy 100
Conclusion 100
References 101
Aberrant Signalling Complexes in GBMs: Prognostic and Therapeutic Implications 103
Introduction 104
Aberrant Growth Factor and Signal Transduction Pathways 106
PDGF/PDGFR 106
EGFR 107
VEGF/VEGFR 108
SF/HGF 111
Integrins 112
MMPs/TIMPs 113
p21-RAS 114
PI3K-PTEN-AKT 115
JAK-STAT 115
PKC 116
Aberrant Cell Cycle Regulatory Pathways 117
p53 and Rb 117
p16/cdk4/cyclinD/pRb 118
Angiogenesis, Invasion, and Apoptosis 118
Therapeutic Implications from Known Aberrant Signalling Pathways 120
Anti-PDGFR molecules 121
Anti-EGFR molecules 122
Anti-VEGF and Anti-VEGFR molecules 122
Anti-SF/HGF molecules 123
Anti-integrins molecules 123
Anti-Ras molecules 123
Anti-MTOR/PI3K inhibitors 124
Anti-PKC 124
Anti-MMPs 125
Future Directions in Biological Therapies 125
References 126
Role of Aberrant Cell Cycle in the Growth and Pathogenesis of Glioblastoma 138
Introduction 138
Genetic Alterations Predispose Glial Progenitor Cells to Oncogenic or Mitogenic Stimuli 140
Astrocyte Differentiation Versus Gliomagenesis: Does Cell Cycle Play an Integral Role? 141
Anomalous Growth Factor Signaling 141
Activation of Akt Pathway 142
Abnormal Cell Cycle Machinery in Glioblastoma 142
Cell Cycle Aberrations Cause Unmitigated Glioblastoma Proliferation 144
The p16-CDK4-Rb Pathway in Cell Cycle 145
The ARF-p53 Pathway in Cell Cycle 146
Epigenetic Alterations and Pathogenesis of Glioblastoma 147
Do Epigenetic Alterations Contribute to Glioblastoma Progression? 147
Can Chromatin Modifiers Induce Epigenetic Variations to Regulate Tumor Suppressor Pathways? 148
Role of Tumor Suppressor in Gliomagenesis 149
Role of Ubiquitin Ligases in Cell Cycle of Glioblastoma 149
Is Apoptosis an Extreme Form of Astrocytic Differentiation? 150
Conclusion 153
References 153
Adult Neural Stem Cells and Gliomagenesis 159
Introduction 159
Organization of the Rodent and Human Subventricular Zones 160
Glial Progenitors in the Adult Human Subcortical White Matter 162
Transformation of the Neural Stem and Progenitor Cells 162
Shared Features of Adult Germinal Regions and Gliomas 163
Cytoskeletal Proteins 164
Tumor Suppressor Genes 164
Growth Factors 165
Transcription Factors 166
Transit-Amplifying C Cells as a Candidate for Glioma Cell-of-Origin 167
Implications for Glioma Therapy 167
Conclusions 168
References 168
Divide and Invade: The Dynamic Cytoskeleton of Glioblastoma Cells 172
Introduction 172
The Cytoskeleton and the Malignant Behavior: Emerging Concepts 173
Emerging Concept 1: Cytoskeletal-Based Organelle Trafficking Pathways Contribute to Tumor Cell Motility and Invasion 173
Emerging Concept 2: Tumor Cell Motility Can Vary Depending on the Experimental Conditions Employed 175
Cytoskeletal Disparities Between GBMs and Astrocytes 175
The Cytoskeleton as a Target for Therapeutic Intervention 179
Concluding Comments 181
References 182
Aberrations of the Epigenome in Gliomas: Novel Targets for Therapy 189
Introduction 189
Epigenetics and Chromatin Modification 190
DNA Methylation 190
Histone Modification 191
Overview of Epigenetic Alterations in Cancer 193
Aberrant DNA Methylation 193
Causes of Histone Modifications 194
Epigenetic Alterations in Astrocytic Malignancies 194
Glioblastoma Multiforme (GBM) 194
Anaplastic Astrocytoma 197
Low-Grade Astrocytoma 197
Epigenetics of Oligodendroglial Tumors 198
Epigenetic Changes in Ependymomas 200
Therapeutic Targeting of Epigenetic Modification 201
Conclusion 203
References 204
Chemotherapy for Glioblastoma: Past, Present, and Future 207
Introduction 207
Traditional Chemotherapy Agents 208
Barriers to Effective Treatment 209
Chemotherapy Resistance 209
Blood Brain Barrier (BBB) 210
Glioblastoma Genetics and Chemosensitivity 211
Adjuvant Chemotherapy for Malignant Gliomas: Historical Perspective 212
Treatment of Glioblastoma at Progression 214
Future Directions 217
References 218
Role of Angiogenesis in the Pathogenesis of Glioblastoma and Antiangiogenic Therapies for Controlling Glioblastoma 221
Introduction 222
Genetic Alterations in Glioblastoma 223
Angiogenesis is a Hallmark of Glioblastoma 225
What Is Angiogenesis? 225
Factors Stimulating Angiogenesis in Glioblastoma 226
VEGF and VEGFR Families 226
PDGF and PDGFR Families 229
FGF and FGFR Families 229
EGF/TGF-a and EGFR Families 230
TGF-b and TGFR Families 230
Angiopoietins 231
Physiological Factors for Inhibition of Angiogenesis 231
Antiangiogenic Therapies for Controlling Glioblastoma 232
Inhibition of RTKs 232
Inhibition of Intracellular Effectors 233
Inhibitors of Ras/MAPK and PI3K/Akt/mTOR Pathways 235
Inhibitors of PKC 235
Gene Therapy for Inhibition of Angiogenesis in Glioblastoma 236
Targeted Antiangiogenic Therapy 237
Vascular Targeted Therapy Using Antiangiogenic Factors in Glioblastoma 237
Local Delivery of Encapsulated Angiogenic Inhibitors to Glioblastoma 238
Combination Therapy for Inhibition of Angiogenesis 238
Miscellaneous Antiangiogenic Therapies for Glioblastoma 240
Intratumoral Therapy for Inhibition of Angiogenesis in Glioblastoma 240
Immunotherapy for Inhibition of Angiogenesis in Glioblastoma 240
Treatments to Target Invasion 240
Conclusion 241
References 241
Antiangiogenic Strategies for the Treatment of Gliomas 246
Introduction 246
Regulation of Angiogenesis in Gliomas 247
Perivascular Organization 248
Proliferation 248
Vascular Regression Followed by Necrosis 248
Angiogenesis 248
Molecular Abnormalities in Gliomas and Angiogenesis 249
Developing Antiangiogenic Treatments for Malignant Gliomas 250
Targeting VEGF 250
Bevacizumab 252
VEGF Trap 254
VEGFR Tyrosine Kinase Inhibitors 255
Targeting PDGF 256
Targeting Protein Kinase C-b 257
Other Antiangiogenic Strategies 257
Challenges in the Development of Antiangiogenic Agents and Surrogate Markers of Response 258
Conclusion 261
References 261
Retinoids for the Treatment of Glioblastoma 267
Introduction 268
Retinoids and Their Mechanisms of Action 269
Anti-tumor Activities of Retinoids: Growth Arrest, Differentiation, and Apoptosis 272
Use of Retinoids in Combination Chemotherapy 275
Clinical Trials of Retinoids in Glioblastoma 276
Future Directions 278
Conclusions 279
References 279
Molecular Mechanisms of Taxol for Induction of Cell Death in Glioblastomas 284
Introduction 285
Causes of Brain Tumors 285
Treatments for Glioblastomas 286
Chemotherapy for Glioblastomas 286
Taxol 287
Molecular Mechanisms of Taxol-Induced Cell Death 288
Mechanism of Cell Cycle Arrest 288
Mechanisms of Taxol for Induction of Apoptosis 289
Formulation of Nanotaxol 290
Molecular Gene Therapy for Glioblastomas 293
References 296
Current Endeavors for Enhancing Efficacy of Paclitaxel for Treatment of Glioblastoma 300
Introduction 300
Challenge of Using Chemotherapeutic Agents for Glioblastoma 301
Paclitaxel to Target Microtubules for Treatment of Glioblastoma 302
Paclitaxel Affects Microtubule Dynamics in Cancer Cells 302
Paclitaxel and Its General Mechanism of Action 303
Prospect of Using Paclitaxel in Treating Glioblastoma 303
Challenges of BBB During Paclitaxel Delivery to Glioblastoma 304
Strategies for Improving Paclitaxel Delivery to Glioblastoma 305
Intraventricular Infusion and Intracerebral Implantation 305
Disruption of the BBB Structure to Enhance Drug Delivery 306
Microbubbles Formulation 306
Inhibition of P-glycoprotein (P-gp) for Transporting Paclitaxel Through BBB 307
Paclitaxel Structure Modification to Escape from P-gp 307
Combination of P-gp Inhibitor and Paclitaxel for Treating Glioblastoma 307
Combination of Retinoid and Paclitaxel for Treatment of Glioblastoma 308
Combination of ATRA or 13-CRA and Paclitaxel for Treating Glioblastoma 309
ATRA or 13-CRA Enhanced the Paclitaxel Sensitivity in Rat C6 Glioblastoma Cells 309
ATRA or 13-CRA Increased the Paclitaxel Sensitivity in Human Glioblastoma T98G and U87MG Cell Lines 310
Combination of ATRA and Paclitaxel for Treatment of Human Glioblastoma T98G Xenografts 310
Combination of ATRA and Paclitaxel Upregulated Bax and Released Proapoptotic Molecules from Mitochondria 311
Combination of ATRA and Paclitaxel Activated Proteases for Site-Specific Cleavage of a-Spectrin in Glioblastoma 312
Combination of ATRA and Paclitaxel for Treatment of Human Glioblastoma U87MG Xenografts 312
Combination Therapy Induced Differentiation and Inhibited Antiapoptotic Signals in Glioblastoma 312
Combination Therapy Activated Stress Kinases in Glioblastoma 313
Combination Therapy Downregulated MEK-2 and Akt Pathways in Glioblastoma 313
Combination Therapy Activated Ligand-Mediated Apoptotic Pathways in Glioblastoma 314
Combination Therapy Activated Mitochondria Mediated Intrinsic Pathway of Apoptosis in Glioblastoma 315
Combination Therapy Activated Cysteine Proteases and Cleaved Specific Substrates for Apoptosis in Glioblastoma 315
Development of Paclitaxel Nanomedicine for Treatment of Glioblastoma 316
Conclusion 318
References 318
Dietary Polyphenols as Preventive and Therapeutic Agents in Glioblastoma 325
Introduction 325
Dietary Polyphenolic Compounds 326
Resveratrol 327
Curcumin 329
Epigallocatechin Gallate (EGCG) 332
Conclusion 333
References 333
Targeting Energy Metabolism in Brain Cancer with Restricted Diets 340
Introduction 340
Metabolic Control Theory/Analysis 341
Adaptability and Variability Selection 342
Energy Metabolism in Brain Tumors 343
Dietary Energy Metabolism and Brain Cancer 345
The Ketogenic Diet 345
Dietary Energy Restriction 346
Dietary Restriction Is Antiangiogenic and Proapoptotic 347
Complicating Issues for Implementing Diet Therapy for Malignant Brain Cancer 350
Guidelines for Implementing Dietary Management of Malignant Brain Cancer 352
Conclusions 354
References 355
Immunotherapy for Glioblastoma 363
Introduction 363
Ag-specific Immunotherapy for Glioblastoma 366
DC Based Immunotherapy for Glioblastoma 368
Cytokine Based Immunotherapy for Glioblastoma 372
Targeting the HLA Class II Pathway for Immune Recognition of Glioblastoma 374
Factors Regulating Immune Recognition of Glioblastoma 376
Tumor-associated molecules 376
Prostaglandin E2 (PGE2) 376
Transforming growth factor-beta (TGF-b) 377
Interleukin-10 (IL-10) 377
Indoleamine 2,3-dioxygenase (IDO) 378
Galectin-1 (Gal-1) 378
Absence of adhesive factors 378
Extracellular matrix (ECM) proteins 378
Intercellular adhesion molecule-1 (ICAM-1) 379
Defects in HLA class I presentation 379
Loss of HLA class I proteins and NK-mediated killing of tumors 379
Factors Augmenting Glioblastoma Vaccination 380
Growth factors to support APC and T cells 380
Agonists to activate APC and T cells 381
Adjuvants to augment tumor vaccines 381
Antibodies to augment antitumor responses 382
T-cell checkpoint blockade inhibitor: anti-programmed death-1 382
Inhibitor of an immunosuppressive enzyme inhibitor: 1-methyl tryptophan 382
T-cell stimulator: anti-CD137 (anti-4-1BB) 383
Conclusions 383
References 384
Potential of Nanobiotechnology in the Management of Glioblastoma Multiforme 396
Introduction 396
Nanobiotechnology and Nanomedicine 397
Nanooncology 398
Nanobiotechnology-Based Imaging of Glioblastoma Multiforme 398
Nanoparticles as MRI Contrast Agents 398
Quantum Dots for PET Imaging of Tumor Vasculature 399
QD-Labeled Antibodies for Visualization of GBM Receptors 399
Nanoparticles as Aid to Intra-operative Visualization of GBM 399
Nanobiotechnology for Anticancer Drug Discovery and Development 400
Role of Nanobiotechnology in Drug Delivery to GBM 400
Nanomaterials as Carriers of Anticancer Drugs for Delivery to GBM 402
Nanoparticles for Delivery of Drugs to GBM across BBB 402
Targeted Delivery of Nanoparticles to Tumors 403
Nanoparticles Targeted to Tumor Receptors 403
Nano-LDL as a Vehicle for Targeted Delivery of Paclitaxel to LDL Receptors 404
Biomimetic Nanoparticles Targeted to Tumors 405
Targeting of GBM with Monoclonal Antibody Linked to Boronated Dendrimer 405
Delivery of Nanoliposomes to GBM 406
Human Interleukin-13-Conjugated Liposomes 406
Immunoliposomes 406
Delivery of Nanoliposomes to GBM using Convection-Enhanced Delivery 407
Antisense Oligonucleotide Delivery Combined with Nanoparticles 407
Combination of Diagnostics with Therapeutics of GBM 408
Multifunctional Nanoparticles for Treating Brain Tumors 408
PEBBLE System for Targeted PDT of GBM 408
Targeted Thermotherapy of GBM 409
Thermotherapy of GBM Using Magnetic Nanoparticles 409
Targeted Thermoablation Using Immunonanoshells 410
Role of Nanoparticles in Gene Therapy of GBM 410
Intravenous Nonviral Gene Delivery with Nanoparticles into Brain Tumors 410
Liposomes as Nonviral Vectors for Gene Therapy of GBM 411
Monitoring of Gene Therapy of GBM by Nanoparticle-Based Brain Imaging 411
Safety of Nanoparticles for Therapeutic Use in GBM 412
Role of Nanobiotechnology in Personalized Management of GBM 412
Concluding Remarks 413
References 414
Index 417