Molecularly Targeted Therapy for Childhood Cancer (eBook)

Peter J. Houghton, Robert J. Arceci (Herausgeber)

eBook Download: PDF

2010 | 2010
XVIII, 536 Seiten
Springer New York (Verlag)
978-0-387-69062-9 (ISBN)

Infos

Each chapter will focus on the known molecular characteristics of specific childhood cancers, focusing on how the molecular 'drivers' can be exploited from a therapeutic standpoint with currently available targeted agents. Where applicable, integration of targeted therapies with conventional cytotoxic agents will be considered.

This volume will provide a comprehensive summary of molecular characteristics of childhood cancers, and how the changes involved in transformation provide us with opportunities for developing relatively less toxic, but curative, therapies.

Inhalt

Acknowledgments 6
Contents 8
Introduction to Targeted Therapy Text 12
Contributors 16
Part I Hematologic Malignancies 20
The Emerging Era of Targeted Therapy in Childhood Acute Lymphoblastic Leukemia 21
The BCR/ABL Tyrosine Kinase and Ph+ ALL 22
The FLT-3 Pathway in MLL Rearranged Infant ALL 24
The Notch Pathway in T-ALL 26
Monoclonal Antibodies in the Treatment of ALL 28
Cancer Stem Cells in ALL 30
Summary 31
References 32
Molecular Targeted Therapies in T-CellAcute Lymphoblastic Leukemia 37
Introduction 37
Oncogenic Transcription Factors 38
NOTCH1 39
The NOTCH1 Pathway 39
Strategies for NOTCH1 Inhibition 41
Resistance to NOTCH1 Inhibitors and Therapeutic Strategies to Overcome Resistance 42
PTEN, PI3K-AKT, and mTOR 44
Tyrosine Kinase Genes 44
RAS 45
Conclusions 46
References 46
Molecularly Targeted Therapy for Infant ALL 49
FLT3 Tyrosine Kinase Inhibition 51
Targeting Anti-apoptotic BCL-2 Family Members 56
Targeting MLL Fusion Transcripts 63
PFWT Targeting of MLL Partner Protein Interactions 63
Targeting Glycogen Synthase Kinase 3 64
HSP90 as a Potential Therapeutic Target 65
Epigenetic Strategies 66
mTOR Inhibition 66
Targeting CD33 Cell Surface Antigen 67
Conclusions 67
References 68
Targeted Therapeutic Approaches for AML 77
Introduction 77
Mechanisms of Leukemogenesis: Implications for Targeted Therapy Development 78
Refining the Definition and Relevance of Targeted Therapy 79
Development of Targeted Therapies for AML 79
Specific Examples of Targeting AML 80
Targeting Pathways that Alter Leukemia Cell Proliferation and Survival 80
Tyrosine Kinases 80
Inhibition of Signaling Pathways Downstream of TK Receptors 84
Drug Resistance Mechanisms and Leukemic Cell Survival 86
Epigenetic and Chromatin Remodeling-Directed Targets 88
Targeted Immunotherapy and Immunostimulatory Therapy 90
Future Challenges 92
References 93
Acute Promyelocytic Leukaemia 101
Introduction 101
Demographic Features 101
Pathogenesis of APL 102
Diagnosis of APL 104
Treatment of APL 106
Induction Therapy 107
Complications of Induction Therapy 108
Consolidation Therapy 110
Maintenance Treatment 112
Molecular Monitoring in APL 112
MRD Detection Is an Independent Predictor of Outcome in APL 112
Real-Time Quantitative RT-PCR Assays Enhance MRD Detection in APL 113
Anthracycline Cumulative Dose and Cardiotoxicity 114
Stem Cell Transplantation 114
Arsenic Trioxide 114
What to Do When Treatment Fails? 115
Extramedullary Relapse 117
New Drugs 118
Conclusions 119
References 119
Down Syndrome and Acute Myeloid Leukemia: An Unique Genetic Sensitivity to Chemotherapy 127
Introduction 127
Chemotherapy Sensitivity and Down Syndrome 129
The Role of Chromosome 21-Localized Genes and Chemotherapy Sensitivity in Down Syndrome AMkL 130
Relationship Between GATA1 and Chemotherapy Drug Sensitivities 133
Differential Gene Expression Studies and Down Syndrome AMkL 134
Future Challenges 135
Conclusion 136
References 136
Targeting RAS Signaling Pathways in Juvenile Myelomonocytic Leukemia (JMML) 141
GM-CSF and Deregulated RAS Signaling in Pathogenesis of JMML 142
Mouse Models 145
Targeted Therapeutics 146
RAF/MEK/ERK 148
PI3K/AKT/mTOR 150
PTPN11/SHP-2 151
JAK2-STAT5 151
Conclusion 152
References 152
Chronic Myeloid Leukemia: Pathophysiology and Therapeutics 157
Pathophysiology of Bcr-Abl in CML 157
Clinical Phases 160
Targeted Therapies 161
Imatinib in Children 163
Monitoring 163
Resistance to Kinase Inhibitors and New Therapeutic Strategies 165
Indications for Transplantation 167
Future Therapies 168
References 168
Molecularly Targeted Therapies in Pediatric Myelodysplastic Syndromes 172
Introduction 172
Myelodysplastic Syndromes 173
Incidence 173
Classification 173
Etiology 174
The Relationship Between Acute Myeloid Leukemia and MDS 180
Chromatin-Based Transcriptional Therapy 181
DNA Methyltransferase (DNMT) Inhibitors 181
Histone Deacetylases (HDACs) and HDAC Inhibitors (HDACi) 183
Maturation-Directed Therapies 184
Immunomodulatory Drugs (IMiDs) and Anti-angiogenic Agents 184
Other Targeted Therapies 185
Combination Therapies 185
Stem Cell Transplantation for Myelodysplastic Syndromes 186
Conclusions 187
References 188
New Therapeutic Frontiers for Childhood Non-Hodgkin Lymphoma 194
Introduction 194
Diffuse Large B-Cell Lymphoma 195
Burkitt Lymphoma 205
Anaplastic Large Cell Lymphoma 209
Lymphoblastic Lymphoma 215
Summary and Future Directions 222
References 223
Molecular Targeting of Post-transplant Lymphoproliferative Disorders 231
Introduction 231
Epstein–Barr Virus Infection of Humans 233
Host Immune Response Against EBV 234
EBV Targets Apoptotic Resistance 236
Molecular Targets for EBV-PTLD 237
Vaccines 237
Anti-Viral Medications 237
Immunosuppression 238
Monoclonal Antibodies 238
T Cell Adoptive Immunotherapy 239
Conclusion 240
References 240
Part II Solid Tumors 245
Molecularly Targeted Therapies for Astrocytomas 246
Introduction 246
Molecular Features of Tumorigenesis 247
Low-Grade Gliomas 247
High-Grade Gliomas 247
Molecularly Based Therapeutic Strategies 250
Inhibitors of Growth Factor Receptors 251
Platelet-Derived Growth Factor Receptor as a Target 251
Epidermal Growth Factor Receptor as a Target 253
Inhibitors of Downstream Signaling 255
Inhibition of RAS Processing 255
Inhibition of Protein Kinase C 257
MAPK Cascade Inhibitors 257
Inhibitors of PI3K/Akt Pathways 258
Inhibition of Angiogenesis 259
VEGFR Inhibition 259
VEGF Blockade 260
Other Angiogenic Agents 260
Interference with Growth Factor Receptor and Survival Signaling May Potentiate Other Therapies 261
Counteracting the Drug Resistance Phenotype 262
Alkylguanine DNA Alkyltransferase Inhibition 262
Base-Excision Repair Inhibition 264
Other Contributors to Drug Resistance 265
Immunological or Ligand-Based Therapies 267
Tf-CRM107 268
IL13-PE38QQR 268
TP-38 270
Future Directions and Challenges 270
References 271
Targeted Therapy in Medulloblastoma in Molecularly Targeted Therapy for Childhood Cancer 281
Introduction 281
Histopathological and Clinical Considerations 281
Risk Stratification 283
Cellular Origins of Medulloblastoma 284
Molecular Features of Medulloblastoma and Targeted Strategies 285
Sonic Hedgehog 286
WNT/b-Catenin 289
NOTCH 290
IGFR 290
CXCR4 292
PI3K/AKT/mTOR 292
EGFR Family 293
PDGFR 294
TRKC 294
HDAC Inhibitors and Retinoic Acid 294
Future Directions and Challenges 295
References 296
Future Treatments of Ependymoma 305
Introduction 305
What Do We Know About Ependymoma? 306
Clinical Issues 306
Epidemiology and Histopathology 306
Current Therapy 306
Tumor Biology 308
Genetics 308
Genomics 308
Cancer Stem Cells and The Origins of Ependymoma 309
Ependymoma Stem Cell Niches 310
Prior Testing of Molecular Targeted Therapies in Ependymoma 311
How Can We Improve the Treatment of Ependymoma? 311
Ependymoma Is not a Single Disease 311
Some Ependymomas May Be Cured with Minimal Conventional Therapy 312
Curing All Patients with Ependymoma Will RequireNew Treatments 312
Future Directions and Challenges 313
References 313
Development of Targeted Therapies for Rhabdoid Tumors Based on the Functions of INI1/hSNF5 Tumor Suppressor 319
Introduction 319
General Features of Rhabdoid Tumors 320
Pathology 320
Diagnosis 320
Current Therapies for Rhabdoid Tumors 321
Ongoing Clinical Trials for RTs 322
Mechanisms of INI1-Mediated Tumor Suppression 324
Regulation of Transcription by INI1 and the SWI/SNF Complex 325
Pathways Affected by Loss of INI1 in Rhabdoid Tumors 326
Induction of G0/G1 Arrest by INI1/hSNF5 327
Role of INI1 in Mitotic Spindle Check-Point 327
INI1/hSNF5 Induces Interferon Signaling and Markers of Senescence 328
Rhabdoid Tumor Cell of Origin and the Role of INI1 in Differentiation 328
INI1’s Involvement in Cellular Differentiation Pathways 329
Therapeutic Targeting of Downstream Effectors of INI1/hSNF5 for Treatment of Rhaboid Tumors 330
Hypothesis for the Mechanism of Tumor Suppression by INI1 330
Critical Role of Cyclin D1 in Rhabdoid Tumor Formation and Survival 331
Development of Novel Therapeutic Strategies Against RTs by Targeting Cyclin/cdk Axis 332
4HPR as a Therapeutic Agent for Rhabdoid Tumors 333
Flavopiridol as a Therapeutic Agent for Rhabdoid Tumors 335
Other Pathways Amenable for Developing Targeted Therapies for RTs 335
Targeting the Mitotic Spindle Checkpoint 336
Targeting the Interferon Signaling Pathway 336
Future Directions and Challenges 337
References 338
Development of Targeted Therapies for Neurofibromatosis Type 1 (NF1) Related Tumors 345
Introduction 345
Genetics and Diagnosis of NF1 345
NF1 Related Tumor Manifestations 347
Dermal Neurofibromas 347
Plexiform Neurofibromas 347
Malignant Peripheral Nerve Sheath Tumors 348
Optic Pathway Gliomas 348
Juvenile Myelomonocytic Leukemia 349
Molecular Features of Tumorigenesis 349
RAS Pathway 349
Cells of Tumor Origin and Tumor Environment 350
Angiogenesis 350
Growth Factors and Growth Factor Receptors 351
Mammalian Target of Rapamcyin (mTOR) 351
Molecular Features for MPNSTs 352
Rationale of Pathways 353
Current Strategies: Development of Targeted Treatments for NF1 Tumors 353
Future Directions and Challenges 357
Preclinical Evaluation of Agents 357
Infrastructure for Clinical Trials 357
Development of Agents for Young Children 358
Evaluation of Effect of Agents on Other NF1 Manifestations 358
Target Validation 358
Combination Therapy 359
References 359
Molecular Therapy for Neuroblastoma 365
Introduction 365
Risk Classification 366
Current Approach to Therapy 367
Locoregional Tumors 367
Metastatic Tumors 368
Strategies to Identify Molecular Targets 369
New Approaches to High Risk Disease 369
Cytotoxic Agents 370
Tyrosine Kinase Inhibitors 371
The Neuroblastoma Stem Cell Conundrum 372
Targeted Delivery of Radionucleotides 373
Immunotherapy 373
Retinoids 374
Angiogenesis Inhibitors 375
Targeting MYCN 375
Mitotic Spindle Inhibition 376
Other Strategies 376
Future Directions and Challenges 377
References 377
Ewing’s Sarcoma Family of Tumors: Molecular Targets Need Arrows 386
Ewing’s Sarcoma Patients Require Improved Therapy 386
Ontogeny of ESFT 386
Models of ESFT 388
An Ideal Molecular Target 389
EWS-FLI1 Modulates Transcription and Splicing 390
Elimination of EWS-FLI1 Reduces ESFT Cell and Tumor Growth 392
Molecular Targeting of ESFT 393
EWS-FLI1: The Perfect Target 393
Small-Molecule Protein–Protein Interaction Inhibitors 393
YK-4-279 is a Novel Small-Molecule Inhibitor of EWS-FLI1 394
Alternate Approaches to Small Molecule Identification 395
Single-Chain Antibodies 395
Targeting the Targets 395
Disruption of EWS-FLI1 DNA Binding 396
Non-EWS-FLI1 ESFT Targets 396
Modulation of Apoptotic Tendency 396
Cytokine-Regulated Growth Pathways 398
Molecular Targets from Other Tumor Models 401
Conclusion 403
References 404
Molecular Targeted Therapy for Wilms’ Tumor 414
Introduction 414
Current Treatment Strategies 414
Molecular Pathways in Wilms Tumor 415
IGF Signaling 417
WNT-b-catenin Pathway 419
EGFR Pathway 421
Angiogenesis 421
Apoptotic Pathways 422
Cell Cycle 423
HGF/c-MET 423
Other Pathways 424
Preclinical Identification of New Agents for Wilms Tumor 425
In Vitro Investigation of WT 425
In Vivo Xenograft Testing in WT 426
Preliminary Anti-EGFR and Angiogenesis Testing 427
Pediatric Preclinical Testing Program WT Xenograft Testing 427
Future Directions and Challenges 428
References 430
Molecular Therapy for Rhabdomyosarcoma 438
Introduction 438
What Is the Cell of Origin? 439
Whole Genome Expression Profiling 440
Chimeric Transcription Factors and Oncogenes 441
PAX3-FKHR 441
MYCN Dysregulation 445
TP53 Dysregulation 447
Aberrant Growth Factor Signaling in RMS 448
Insulin-Like Growth Factor Signaling 448
Hepatocyte Growth Factor/MET Autocrine Signaling 452
Hedgehog Signaling Pathway 454
Other Pathways (RAS/MAPK/c-KIT) 454
Differentiation 455
Angiogenesis 456
Future Directions and Challenges 458
References 459
Molecularly Targeted Therapy for Osteosarcoma: Where Do We Go from Here? 472
Introduction/Epidemiology 472
Molecular Features of Tumorigenesis: Alterations in Osteosarcoma 473
Osteosarcoma Cell of Origin 473
Cancer Predisposition Syndromes 474
Viral Targeting of Tumor Antigens 476
Murine Models 476
Cell Cycle Regulation 477
Growth Factors/Signal Transduction Pathways 479
Signal Transduction 481
Other Oncogenes 484
Genetic Complexity 485
Immortalization 485
Bone Differentiation 486
Metastasis 488
Angiogenesis 488
Drug Resistance 489
Rationale for Targeting Specific Pathways 490
Current Strategies 491
Targeting Bone Differentiation Pathways 498
The Pediatric Preclinical Testing Program 499
Summary 500
References 500
Nonrhabdomyosarcoma Soft Tissue Sarcoma in Children: Developing New Treatments Based on a Better Understanding of Disease Biology 512
Introduction 512
NRSTS Biology 514
Two Fundamental Groups of NRSTS 514
What Is the Cellular Origin of NRSTS? 515
Coupling Molecular Biology to Targeted Therapy for Childhood NRSTS 515
Synovial Sarcoma and the SYT-SSX Gene Fusions 515
Malignant Peripheral Nerve Sheath Tumor and NF1 Mutation 517
Infantile Fibrosarcoma and the ETV6-NTRK3 Fusion Protein 519
Malignant Fibrous Histiocytoma 520
Dermatofibrosarcoma Protuberans and the COL1A1-PDGFB Fusion 521
Gastrointestinal Stromal Tumor and Activation of cKIT and PDGFR 521
Inflammatory Myofibroblastic Tumor and ALK Activation 523
Leiomyosarcoma 524
Current Clinical Trials Using Targeted Therapies for Childhood NRSTS 525
Future Directions and Challenges 526
References 526
Index 533

Produkt-Details

• Erscheint lt. Verlag: 10.9.2010
• Zusatzinfo: XVIII, 536 p.
• Verlagsort: New York
• Sprache: englisch
• Themenwelt: Medizin / Pharmazie ► Medizinische Fachgebiete ► Onkologie
• Themenwelt: Medizin / Pharmazie ► Medizinische Fachgebiete ► Pädiatrie
• Themenwelt: Studium ► 1. Studienabschnitt (Vorklinik) ► Biochemie / Molekularbiologie
• Themenwelt: Studium ► 2. Studienabschnitt (Klinik) ► Humangenetik
• Themenwelt: Naturwissenschaften ► Biologie
• Themenwelt: Technik
• Schlagworte: Biology • Cancer • Childhood • Development • leukemia • Lymphoma • Physiology • targeted therapy • tissue • Tumor • Tumors
• ISBN-10: 0-387-69062-X / 038769062X
• ISBN-13: 978-0-387-69062-9 / 9780387690629