Glioblastoma:

Molecular Mechanisms of Pathogenesis and Current Therapeutic Strategies
1. Auflage 2009
ISBN: 978-1-4419-0410-2
Verlag: Springer-Verlag
Format: PDF
Kopierschutz: Wasserzeichen (»Systemvoraussetzungen)

E-Book, Englisch, 431 Seiten

Glioblastoma is the most malignant brain tumor that still remains incurable. It is such a deadly disease that patients do not survive more than a few months after diagnosis. Our understanding of the histopathology and molecular mechanisms of formation of glioblastoma is rapidly advancing so as to provide us clues for devising rational therapeutic strategies for treatment of this malignancy. It is important that we continue to improve our knowledge about the pathogenesis of this devastating disease and explore new areas to find successful therapeutic strategies. Various approaches such as sophisticated imaging techniques, improved surgical procedures, ground-breaking strategies for radiotherapy, chemotherapy, immunotherapy, chemoimmunotherapy, and photodynamic therapy are being used for eradicating glioblastoma. Hopefully, this book will be an important source of information on glioblastoma and therefore be highly useful to the students, postdoctoral fellows, principal investigators, and clinicians involved in this field.

Autoren/Hrsg.

Inhaltsverzeichnis

1;Preface;5
2;Contents;6
3;Contributors;8
4;Overview of the Molecular Genetics and Molecular Chemotherapy of GBM;11
4.1;Introduction;12
4.2;Growth Factor Signaling – PDGF and PDGFR;13
4.3;Growth Factor Signaling – EGF and EGFR;17
4.4;Ras Signaling;23
4.5;Raf/MEK Signaling;26
4.6;PI3K/Akt Signaling;28
4.7;mTOR Signaling;32
4.8;Angiogenesis and Vascular Endothelial Growth Factor;35
4.9;Multitargeted Molecular Chemotherapeutic Agents;40
4.10;Future Directions;41
4.11;References;42
5;Primary Brain Tumors: Characteristics, Practical Diagnostic and Treatment Approaches;53
5.1;Introduction;54
5.2;Neuroepithelial Tumors;55
5.2.1;Localized Gliomas: Pilocytic Astrocytoma and Subependymal Giant Cell Astrocytoma (WHO Grade I, Low Grade Astrocytoma);55
5.2.2;Diffuse Gliomas: Diffuse Astrocytoma, Oligodendroglioma, Oligoastrocytoma (WHO Grade II, Low Grade), Anaplastic Astrocytoma, An;56
5.2.2.1;Diffuse Astrocytoma (WHO Grade II, Low-Grade Astrocytoma);56
5.2.2.2;Oligodendroglioma and Oligoastrocytomas (Grade II, Low-Grade Oligodendroglial Tumors);57
5.2.3;Treatment;59
5.2.3.1;Surgery;60
5.2.3.2;Radiation Therapy;61
5.2.3.3;Chemotherapy;63
5.3;Malignant Gliomas: Anaplastic Astrocytoma, Anaplastic Oligodendroglioma, Anaplastic Oligoastrocytoma (WHO Grade III, High Grade;64
5.3.1;Anaplastic Astrocytoma (Grade III Astrocytoma) and Glioblastoma Multiforme (Grade IV Astrocytoma);65
5.3.2;Anaplastic Oligodendroglioma and Anaplastic Oligoastrocytoma (Grade III Oligodendroglioma and Grade III Oligoastrocytoma);66
5.3.3;Treatment;67
5.3.3.1;Surgery;67
5.3.3.2;Radiation;67
5.3.3.3;Chemotherapy;67
5.3.3.3.1;Temozolomide;69
5.3.3.3.2;Nitrosoureas;70
5.3.3.3.2.1;BCNU (Carmustine);70
5.3.3.3.2.2;CCNU (Lomustine);71
5.3.3.3.3;Platinum Compounds;71
5.3.3.3.3.1;Carboplatin;71
5.3.3.3.4;PCV (Procarbazine, CCNU, Vincristine);71
5.3.3.3.5;Tamoxifen;72
5.3.3.4;Molecular Targeted Therapy;72
5.3.3.4.1;Bevacizumab (Avastin);72
5.3.3.4.2;Erlotinib (Tarceva);73
5.4;Other Neuroepithelial Tumors;73
5.4.1;Ependymoma;73
5.4.2;Treatment;74
5.5;Non-neuroepithelial Tumors;75
5.5.1;Meningioma;75
5.5.2;Treatment;76
5.5.2.1;Surgery;76
5.5.2.2;Radiation;76
5.5.2.3;Chemotherapy/Immunotherapy;76
5.5.2.3.1;Recombinant Interferon (IFN-alpha-2b);77
5.5.2.3.2;Hydroxyurea;77
5.5.2.3.3;Somatostatin;77
5.6;Primary Central Nervous System Lymphoma;77
5.6.1;Treatment;79
5.6.1.1;Surgery;79
5.6.1.2;Radiation;79
5.6.1.3;Chemotherapy;80
5.6.1.3.1;High-Dose Methotrexate;80
5.6.1.4;Rituximab;80
5.7;References;81
6;Pathology of Glioblastoma Multiforme;86
6.1;Introduction;86
6.2;General Features;87
6.3;Macroscopy;88
6.4;Microscopy;88
6.5;Immunohistochemistry;91
6.6;Differential Diagnosis;92
6.7;Prognostic Factors;93
6.8;References;93
7;Molecular Mechanisms of Pathogenesis in Glioblastoma and Current Therapeutic Strategies;94
7.1;Introduction;94
7.2;Grading;95
7.3;Stem Cells;96
7.4;Invasiveness;97
7.5;Glioblastoma;98
7.6;Genetics;98
7.7;Necrosis;99
7.8;Angiogenesis;99
7.9;Traditional and Innovative Therapy;100
7.10;Conclusion;100
7.11;References;101
8;Aberrant Signalling Complexes in GBMs: Prognostic and Therapeutic Implications;103
8.1;Introduction;104
8.2;Aberrant Growth Factor and Signal Transduction Pathways;106
8.2.1;PDGF/PDGFR;106
8.2.2;EGFR;107
8.2.3;VEGF/VEGFR;108
8.2.4;SF/HGF;111
8.2.5;Integrins;112
8.2.6;MMPs/TIMPs;113
8.2.7;p21-RAS;114
8.2.8;PI3K-PTEN-AKT;115
8.2.9;JAK-STAT;115
8.2.10;PKC;116
8.3;Aberrant Cell Cycle Regulatory Pathways;117
8.3.1;p53 and Rb;117
8.3.2;p16/cdk4/cyclinD/pRb;118
8.4;Angiogenesis, Invasion, and Apoptosis;118
8.5;Therapeutic Implications from Known Aberrant Signalling Pathways;120
8.5.1;Anti-PDGFR molecules;121
8.5.2;Anti-EGFR molecules;122
8.5.3;Anti-VEGF and Anti-VEGFR molecules;122
8.5.4;Anti-SF/HGF molecules;123
8.5.5;Anti-integrins molecules;123
8.5.6;Anti-Ras molecules;123
8.5.7;Anti-MTOR/PI3K inhibitors;124
8.5.8;Anti-PKC;124
8.5.9;Anti-MMPs;125
8.6;Future Directions in Biological Therapies;125
8.7;References;126
9;Role of Aberrant Cell Cycle in the Growth and Pathogenesis of Glioblastoma;138
9.1;Introduction;138
9.2;Genetic Alterations Predispose Glial Progenitor Cells to Oncogenic or Mitogenic Stimuli;140
9.3;Astrocyte Differentiation Versus Gliomagenesis: Does Cell Cycle Play an Integral Role?;141
9.3.1;Anomalous Growth Factor Signaling;141
9.3.2;Activation of Akt Pathway;142
9.4;Abnormal Cell Cycle Machinery in Glioblastoma;142
9.4.1;Cell Cycle Aberrations Cause Unmitigated Glioblastoma Proliferation;144
9.4.2;The p16-CDK4-Rb Pathway in Cell Cycle;145
9.4.3;The ARF-p53 Pathway in Cell Cycle;146
9.5;Epigenetic Alterations and Pathogenesis of Glioblastoma;147
9.5.1;Do Epigenetic Alterations Contribute to Glioblastoma Progression?;147
9.5.2;Can Chromatin Modifiers Induce Epigenetic Variations to Regulate Tumor Suppressor Pathways?;148
9.5.3;Role of Tumor Suppressor in Gliomagenesis;149
9.5.4;Role of Ubiquitin Ligases in Cell Cycle of Glioblastoma;149
9.6;Is Apoptosis an Extreme Form of Astrocytic Differentiation?;150
9.7;Conclusion;153
9.8;References;153
10;Adult Neural Stem Cells and Gliomagenesis;159
10.1;Introduction;159
10.2;Organization of the Rodent and Human Subventricular Zones;160
10.3;Glial Progenitors in the Adult Human Subcortical White Matter;162
10.4;Transformation of the Neural Stem and Progenitor Cells;162
10.5;Shared Features of Adult Germinal Regions and Gliomas;163
10.5.1;Cytoskeletal Proteins;164
10.5.2;Tumor Suppressor Genes;164
10.5.3;Growth Factors;165
10.5.4;Transcription Factors;166
10.6;Transit-Amplifying C Cells as a Candidate for Glioma Cell-of-Origin;167
10.7;Implications for Glioma Therapy;167
10.8;Conclusions;168
10.9;References;168
11;Divide and Invade: The Dynamic Cytoskeleton of Glioblastoma Cells;172
11.1;Introduction;172
11.2;The Cytoskeleton and the Malignant Behavior: Emerging Concepts;173
11.2.1;Emerging Concept 1: Cytoskeletal-Based Organelle Trafficking Pathways Contribute to Tumor Cell Motility and Invasion;173
11.2.2;Emerging Concept 2: Tumor Cell Motility Can Vary Depending on the Experimental Conditions Employed;175
11.3;Cytoskeletal Disparities Between GBMs and Astrocytes;175
11.4;The Cytoskeleton as a Target for Therapeutic Intervention;179
11.5;Concluding Comments;181
11.6;References;182
12;Aberrations of the Epigenome in Gliomas: Novel Targets for Therapy;189
12.1;Introduction;189
12.2;Epigenetics and Chromatin Modification;190
12.2.1;DNA Methylation;190
12.2.2;Histone Modification;191
12.3;Overview of Epigenetic Alterations in Cancer;193
12.3.1;Aberrant DNA Methylation;193
12.3.2;Causes of Histone Modifications;194
12.4;Epigenetic Alterations in Astrocytic Malignancies;194
12.4.1;Glioblastoma Multiforme (GBM);194
12.4.2;Anaplastic Astrocytoma;197
12.4.3;Low-Grade Astrocytoma;197
12.5;Epigenetics of Oligodendroglial Tumors;198
12.6;Epigenetic Changes in Ependymomas;200
12.7;Therapeutic Targeting of Epigenetic Modification;201
12.8;Conclusion;203
12.9;References;204
13;Chemotherapy for Glioblastoma: Past, Present, and Future;207
13.1;Introduction;207
13.2;Traditional Chemotherapy Agents;208
13.3;Barriers to Effective Treatment;209
13.3.1;Chemotherapy Resistance;209
13.3.2;Blood Brain Barrier (BBB);210
13.4;Glioblastoma Genetics and Chemosensitivity;211
13.5;Adjuvant Chemotherapy for Malignant Gliomas: Historical Perspective;212
13.6;Treatment of Glioblastoma at Progression;214
13.7;Future Directions;217
13.8;References;218
14;Role of Angiogenesis in the Pathogenesis of Glioblastoma and Antiangiogenic Therapies for Controlling Glioblastoma;221
14.1;Introduction;222
14.2;Genetic Alterations in Glioblastoma;223
14.3;Angiogenesis is a Hallmark of Glioblastoma;225
14.3.1;What Is Angiogenesis?;225
14.3.2;Factors Stimulating Angiogenesis in Glioblastoma;226
14.3.2.1;VEGF and VEGFR Families;226
14.3.2.2;PDGF and PDGFR Families;229
14.3.2.3;FGF and FGFR Families;229
14.3.2.4;EGF/TGF-a and EGFR Families;230
14.3.2.5;TGF-b and TGFR Families;230
14.3.2.6;Angiopoietins;231
14.3.3;Physiological Factors for Inhibition of Angiogenesis;231
14.4;Antiangiogenic Therapies for Controlling Glioblastoma;232
14.4.1;Inhibition of RTKs;232
14.4.2;Inhibition of Intracellular Effectors;233
14.4.2.1;Inhibitors of Ras/MAPK and PI3K/Akt/mTOR Pathways;235
14.4.2.2;Inhibitors of PKC;235
14.4.3;Gene Therapy for Inhibition of Angiogenesis in Glioblastoma;236
14.4.4;Targeted Antiangiogenic Therapy;237
14.4.4.1;Vascular Targeted Therapy Using Antiangiogenic Factors in Glioblastoma;237
14.4.4.2;Local Delivery of Encapsulated Angiogenic Inhibitors to Glioblastoma;238
14.4.5;Combination Therapy for Inhibition of Angiogenesis;238
14.4.6;Miscellaneous Antiangiogenic Therapies for Glioblastoma;240
14.4.6.1;Intratumoral Therapy for Inhibition of Angiogenesis in Glioblastoma;240
14.4.6.2;Immunotherapy for Inhibition of Angiogenesis in Glioblastoma;240
14.4.6.3;Treatments to Target Invasion;240
14.5;Conclusion;241
14.6;References;241
15;Antiangiogenic Strategies for the Treatment of Gliomas;246
15.1;Introduction;246
15.2;Regulation of Angiogenesis in Gliomas;247
15.2.1;Perivascular Organization;248
15.2.2;Proliferation;248
15.2.3;Vascular Regression Followed by Necrosis;248
15.2.4;Angiogenesis;248
15.3;Molecular Abnormalities in Gliomas and Angiogenesis;249
15.4;Developing Antiangiogenic Treatments for Malignant Gliomas;250
15.4.1;Targeting VEGF;250
15.4.1.1;Bevacizumab;252
15.4.1.2;VEGF Trap;254
15.4.2;VEGFR Tyrosine Kinase Inhibitors;255
15.4.3;Targeting PDGF;256
15.4.4;Targeting Protein Kinase C-b;257
15.4.5;Other Antiangiogenic Strategies;257
15.5;Challenges in the Development of Antiangiogenic Agents and Surrogate Markers of Response;258
15.6;Conclusion;261
15.7;References;261
16;Retinoids for the Treatment of Glioblastoma;267
16.1;Introduction;268
16.2;Retinoids and Their Mechanisms of Action;269
16.3;Anti-tumor Activities of Retinoids: Growth Arrest, Differentiation, and Apoptosis;272
16.4;Use of Retinoids in Combination Chemotherapy;275
16.5;Clinical Trials of Retinoids in Glioblastoma;276
16.6;Future Directions;278
16.7;Conclusions;279
16.8;References;279
17;Molecular Mechanisms of Taxol for Induction of Cell Death in Glioblastomas;284
17.1;Introduction;285
17.2;Causes of Brain Tumors;285
17.3;Treatments for Glioblastomas;286
17.4;Chemotherapy for Glioblastomas;286
17.4.1;Taxol;287
17.5;Molecular Mechanisms of Taxol-Induced Cell Death;288
17.5.1;Mechanism of Cell Cycle Arrest;288
17.5.2;Mechanisms of Taxol for Induction of Apoptosis;289
17.6;Formulation of Nanotaxol;290
17.7;Molecular Gene Therapy for Glioblastomas;293
17.8;References;296
18;Current Endeavors for Enhancing Efficacy of Paclitaxel for Treatment of Glioblastoma;300
18.1;Introduction;300
18.2;Challenge of Using Chemotherapeutic Agents for Glioblastoma;301
18.3;Paclitaxel to Target Microtubules for Treatment of Glioblastoma;302
18.4;Paclitaxel Affects Microtubule Dynamics in Cancer Cells;302
18.5;Paclitaxel and Its General Mechanism of Action;303
18.6;Prospect of Using Paclitaxel in Treating Glioblastoma;303
18.7;Challenges of BBB During Paclitaxel Delivery to Glioblastoma;304
18.8;Strategies for Improving Paclitaxel Delivery to Glioblastoma;305
18.8.1;Intraventricular Infusion and Intracerebral Implantation;305
18.8.2;Disruption of the BBB Structure to Enhance Drug Delivery;306
18.8.3;Microbubbles Formulation;306
18.8.4;Inhibition of P-glycoprotein (P-gp) for Transporting Paclitaxel Through BBB;307
18.8.4.1;Paclitaxel Structure Modification to Escape from P-gp;307
18.8.4.2;Combination of P-gp Inhibitor and Paclitaxel for Treating Glioblastoma;307
18.9;Combination of Retinoid and Paclitaxel for Treatment of Glioblastoma;308
18.9.1;Combination of ATRA or 13-CRA and Paclitaxel for Treating Glioblastoma;309
18.9.1.1;ATRA or 13-CRA Enhanced the Paclitaxel Sensitivity in Rat C6 Glioblastoma Cells;309
18.9.1.2;ATRA or 13-CRA Increased the Paclitaxel Sensitivity in Human Glioblastoma T98G and U87MG Cell Lines;310
18.9.1.3;Combination of ATRA and Paclitaxel for Treatment of Human Glioblastoma T98G Xenografts;310
18.9.1.4;Combination of ATRA and Paclitaxel Upregulated Bax and Released Proapoptotic Molecules from Mitochondria;311
18.9.1.5;Combination of ATRA and Paclitaxel Activated Proteases for Site-Specific Cleavage of a-Spectrin in Glioblastoma;312
18.10;Combination of ATRA and Paclitaxel for Treatment of Human Glioblastoma U87MG Xenografts;312
18.10.1;Combination Therapy Induced Differentiation and Inhibited Antiapoptotic Signals in Glioblastoma;312
18.10.2;Combination Therapy Activated Stress Kinases in Glioblastoma;313
18.10.3;Combination Therapy Downregulated MEK-2 and Akt Pathways in Glioblastoma;313
18.10.4;Combination Therapy Activated Ligand-Mediated Apoptotic Pathways in Glioblastoma;314
18.10.5;Combination Therapy Activated Mitochondria Mediated Intrinsic Pathway of Apoptosis in Glioblastoma;315
18.10.6;Combination Therapy Activated Cysteine Proteases and Cleaved Specific Substrates for Apoptosis in Glioblastoma;315
18.11;Development of Paclitaxel Nanomedicine for Treatment of Glioblastoma;316
18.12;Conclusion;318
18.13;References;318
19;Dietary Polyphenols as Preventive and Therapeutic Agents in Glioblastoma;325
19.1;Introduction;325
19.2;Dietary Polyphenolic Compounds;326
19.2.1;Resveratrol;327
19.2.2;Curcumin;329
19.2.3;Epigallocatechin Gallate (EGCG);332
19.3;Conclusion;333
19.4;References;333
20;Targeting Energy Metabolism in Brain Cancer with Restricted Diets;340
20.1;Introduction;340
20.2;Metabolic Control Theory/Analysis;341
20.3;Adaptability and Variability Selection;342
20.4;Energy Metabolism in Brain Tumors;343
20.5;Dietary Energy Metabolism and Brain Cancer;345
20.5.1;The Ketogenic Diet;345
20.5.2;Dietary Energy Restriction;346
20.6;Dietary Restriction Is Antiangiogenic and Proapoptotic;347
20.7;Complicating Issues for Implementing Diet Therapy for Malignant Brain Cancer;350
20.8;Guidelines for Implementing Dietary Management of Malignant Brain Cancer;352
20.9;Conclusions;354
20.10;References;355
21;Immunotherapy for Glioblastoma;363
21.1;Introduction;363
21.2;Ag-specific Immunotherapy for Glioblastoma;366
21.3;DC Based Immunotherapy for Glioblastoma;368
21.4;Cytokine Based Immunotherapy for Glioblastoma;372
21.5;Targeting the HLA Class II Pathway for Immune Recognition of Glioblastoma;374
21.6;Factors Regulating Immune Recognition of Glioblastoma;376
21.6.1;Tumor-associated molecules;376
21.6.1.1;Prostaglandin E2 (PGE2);376
21.6.1.2;Transforming growth factor-beta (TGF-b);377
21.6.1.3;Interleukin-10 (IL-10);377
21.6.1.4;Indoleamine 2,3-dioxygenase (IDO);378
21.6.1.5;Galectin-1 (Gal-1);378
21.6.2;Absence of adhesive factors;378
21.6.2.1;Extracellular matrix (ECM) proteins;378
21.6.2.2;Intercellular adhesion molecule-1 (ICAM-1);379
21.6.2.3;Defects in HLA class I presentation;379
21.6.3;Loss of HLA class I proteins and NK-mediated killing of tumors;379
21.7;Factors Augmenting Glioblastoma Vaccination;380
21.7.1;Growth factors to support APC and T cells;380
21.7.2;Agonists to activate APC and T cells;381
21.7.3;Adjuvants to augment tumor vaccines;381
21.7.4;Antibodies to augment antitumor responses;382
21.7.5;T-cell checkpoint blockade inhibitor: anti-programmed death-1;382
21.7.6;Inhibitor of an immunosuppressive enzyme inhibitor: 1-methyl tryptophan;382
21.7.7;T-cell stimulator: anti-CD137 (anti-4-1BB);383
21.8;Conclusions;383
21.9;References;384
22;Potential of Nanobiotechnology in the Management of Glioblastoma Multiforme;396
22.1;Introduction;396
22.2;Nanobiotechnology and Nanomedicine;397
22.3;Nanooncology;398
22.4;Nanobiotechnology-Based Imaging of Glioblastoma Multiforme;398
22.4.1;Nanoparticles as MRI Contrast Agents;398
22.4.2;Quantum Dots for PET Imaging of Tumor Vasculature;399
22.4.3;QD-Labeled Antibodies for Visualization of GBM Receptors;399
22.4.4;Nanoparticles as Aid to Intra-operative Visualization of GBM;399
22.5;Nanobiotechnology for Anticancer Drug Discovery and Development;400
22.6;Role of Nanobiotechnology in Drug Delivery to GBM;400
22.6.1;Nanomaterials as Carriers of Anticancer Drugs for Delivery to GBM;402
22.6.2;Nanoparticles for Delivery of Drugs to GBM across BBB;402
22.6.3;Targeted Delivery of Nanoparticles to Tumors;403
22.6.3.1;Nanoparticles Targeted to Tumor Receptors;403
22.6.3.2;Nano-LDL as a Vehicle for Targeted Delivery of Paclitaxel to LDL Receptors;404
22.6.3.3;Biomimetic Nanoparticles Targeted to Tumors;405
22.6.3.4;Targeting of GBM with Monoclonal Antibody Linked to Boronated Dendrimer;405
22.6.4;Delivery of Nanoliposomes to GBM;406
22.6.4.1;Human Interleukin-13-Conjugated Liposomes;406
22.6.4.2;Immunoliposomes;406
22.6.4.3;Delivery of Nanoliposomes to GBM using Convection-Enhanced Delivery;407
22.6.5;Antisense Oligonucleotide Delivery Combined with Nanoparticles;407
22.7;Combination of Diagnostics with Therapeutics of GBM;408
22.7.1;Multifunctional Nanoparticles for Treating Brain Tumors;408
22.7.2;PEBBLE System for Targeted PDT of GBM;408
22.8;Targeted Thermotherapy of GBM;409
22.8.1;Thermotherapy of GBM Using Magnetic Nanoparticles;409
22.8.2;Targeted Thermoablation Using Immunonanoshells;410
22.9;Role of Nanoparticles in Gene Therapy of GBM;410
22.9.1;Intravenous Nonviral Gene Delivery with Nanoparticles into Brain Tumors;410
22.9.2;Liposomes as Nonviral Vectors for Gene Therapy of GBM;411
22.9.3;Monitoring of Gene Therapy of GBM by Nanoparticle-Based Brain Imaging;411
22.10;Safety of Nanoparticles for Therapeutic Use in GBM;412
22.11;Role of Nanobiotechnology in Personalized Management of GBM;412
22.12;Concluding Remarks;413
22.13;References;414
23;Index;417