Epigenetic cancer therapy:
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| Format: | Book |
| Language: | English |
| Published: |
Amsterdam ; Heidelberg [u.a.]
Academic Press
2015
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| Series: | Translational epigenetics series
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| Subjects: | |
| Online Access: | Inhaltsverzeichnis |
| Physical Description: | XXVI, 721 S. Ill., graph. Darst. 23 cm |
| ISBN: | 9780128002063 |
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| 245 | 1 | 0 | |a Epigenetic cancer therapy |c edited by Steven G. Gray |
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| adam_text | Titel: Epigenetic cancer therapy
Autor: Gray, Steven D
Jahr: 2015
Contents
List of Contributors..............................................................................................................................xxi
CHAPTER 1 Introduction..................................................................................1
Steven G. Gray
t Introduction to the Area (Key Concepts).....................................................................2
2 Epigenetics and Cancer................................................................................................3
3 Targeting Aberrant Epigenetics....................................................................................3
4 Issues to Overcome/Areas of Concern.........................................................................4
5 Future Directions: Translation to the Clinic.................................................................4
References....................................................................................................................5
PART 1 INTRODUCTION AND KEY CONCEPTS_
CHAPTER 2 DNA Methylation and Hydroxymethylation in Cancer.......................9
Fazila Asmar, Alexandra S0gaard, and Kirsten Gr0nbcek
1 Introduction................................................................................................................10
2 Epigenetics.................................................................................................................10
2.1 Chromatin Structure............................................................................................10
2.2 DNA Methylation in Cellular Homeostasis........................................................11
2.3 DNA Demethylation...........................................................................................14
3 DNA Methylation Patterns in Cancer........................................................................16
3.1 Hy permethylation inCancer...............................................................................16
3.2 Hypomethylation in Cancer................................................................................18
3.3 Methods for 5mC Detection................................................................................18
4 Aberrations of Enzymes Involved in DNA Methylation Homeostasis in Cancer......19
4.1 DNA Methyltransferase......................................................................................19
4.2 TET Proteins.......................................................................................................20
4.3 Isocitrate Dehydrogenases..................................................................................21
4.4 Succinate Dehydrogenases..................................................................................23
5 DNA Hydroxymethylation in Cancer........................................................................23
5.1 Methods for 5hmC Detection..............................................................................23
5.2 DNA Hydroxymethylation Patterns in Cancer....................................................25
6 Conclusion..................................................................................................................26
References..................................................................................................................26
V
vi Contents
CHAPTER 3 WRITERS, READERS, AND ERASERS OF EPIGENETIC MARKS..........31
Thomas B. Nicholson, Nicolas Veland, and Taiping Chen
1 Introduction................................................................................................................32
2 Writers........................................................................................................................32
2.1 DNA Methyltransferases.....................................................................................32
2.2 Histone Lysine Methyltransferases.....................................................................33
2.3 Protein Arginine Methyltransferases...................................................................36
2.4 Histone Acetyltransferases..................................................................................38
3 Readers.......................................................................................................................40
3.1 Methyl-CpG-Binding Proteins............................................................................41
3.2 Histone Methylation-Binding Domains.............................................................41
3.3 Histone Acetylation-Binding Domains...............................................................42
4 Erasers........................................................................................................................43
4.1 Proteins Involved in DNA Demethylation..........................................................43
4.2 Histone Demethylases.........................................................................................43
4.3 Histone Deacetylases (HDACs)..........................................................................46
5 Interactions between the Various Components..........................................................47
6 Epigenetics and Cancer..............................................................................................49
6.1 DNA Methylation and Cancer.............................................................................49
6.2 Histone Methylation and Cancer.........................................................................50
6.3 Histone Acetylation and Cancer..........................................................................51
7 Epigenetic Proteins as Therapeutic Targets................................................................52
8 Conclusion and Future Opportunities........................................................................54
References..................................................................................................................54
CHAPTER 4 MicroRNAs and Cancer...............................................................67
Stephen G. Maher, Becky A. S. Bibby, Hannah L. Moody, and Glen Reid
1 miRNA Biogenesis and Functionality........................................................................67
2 miRNAs in Cancer Biology.......................................................................................70
3 miRNA: An Epigenetic Perspective...........................................................................72
3.1 Epigenetic Alteration of miRNA Expression......................................................74
3.2 Epi-miRNA.........................................................................................................75
3.3 miRNA with Epigenetic Functions.....................................................................76
4 miRNA Epigenetic Therapy.......................................................................................77
4.1 miRNA Inhibition in Cancer...............................................................................77
4.2 miRNA Replacement in Cancer..........................................................................82
4.3 Small-Molecule-Based miRNA Modulation.......................................................83
5 Future Perspectives....................................................................................................83
Acknowledgments......................................................................................................84
References..................................................................................................................84
Contents vii
CHAPTER 5 Long Noncoding RNAs and Cancer...............................................91
Casey M. Wright
1 Introduction................................................................................................................92
2 Classification and Nomenclature of IncRNAs...........................................................93
2.1 Classification.......................................................................................................93
2.2 Nomenclature......................................................................................................94
3 Mechanisms of IncRNA Function..............................................................................95
3.1 IncRNAs as Decoys and Guides..........................................................................96
3.2 IncRNAs as Scaffolds..........................................................................................96
3.3 IncRNAs as Signaling Molecules........................................................................97
3.4 miRNA Sequestration.........................................................................................98
3.5 IncRNAs and Epigenetic Regulation...................................................................99
4 IncRNAs and Human Disease..................................................................................100
4.1 Prognostic Markers...........................................................................................101
5 Methods for Studying IncRNA Expression..............................................................103
5.1 High-Throughput Analysis for Discovery.........................................................103
5.2 Verification of Single Candidates Identified from High-Throughput
Data...................................................................................................................105
5.3 Studying the Interactions Between IncRNAs and Protein................................105
6 Strategies for Manipulating IncRNA Expression.....................................................106
6.1 Oligonucleotide-Based Methods.......................................................................106
6.2 RNA Interference..............................................................................................106
6.3 Targeting IncRNAs with Natural Antisense Transcripts...................................106
6.4 Targeting IncRNAs with Small Molecule Inhibitors.........................................107
7 Conclusions..............................................................................................................108
References................................................................................................................108
CHAPTER 6 Ribosomal RNA Methylation and Cancer.....................................115
Gabriel Therizols, Florian Laforets, Virginie Marcel, Frederic Catez, Philippe
Bouvet, and Jean-Jacques Diaz
1 Introduction..............................................................................................................115
2 Overview of Human Ribosome Biogenesis: An Intense Energy
Consuming Process..................................................................................................118
3 Transcriptional and Epigenetic Deregulation of rDNA Gene Expression
in Cancer..................................................................................................................118
3.1 Organization of rDNA Genes and Their Transcription.....................................118
3.2 Targeting rDNA Transcription for Anticancer Drug Development...................121
4 Chemical Modifications of rRNA............................................................................122
4.1 The rRNA Pseudouridylation Machinery..........................................................122
4.2 The rRNA 2 -0-Methylation Machinery..........................................................122
viii Contents
5 Function of rRNA Methylation................................................................................126
5.1 The Complex Functional Architecture of the Ribosome...................................126
5.2 Regulatory Role of rRNA Methylation: An Emerging Concept.......................127
6 Modification of rRNA Methylation in Cancer.........................................................129
6.1 Alterations of snoRNA Expression in Cancer...................................................129
6.2 Deregulation of Gene Expression Coding for rRNA Methylation Complex
Proteins..............................................................................................................130
7 Concluding Remarks................................................................................................132
References................................................................................................................132
CHAPTER 7 Mining the Epigenetic Landscape: Surface Mining or Deep
Underground............................................................................141
Viren Amin, Vitor Onuchic, and Aleksandar Milosavljevic
t Introduction..............................................................................................................142
2 Summary of Epigenomic Profiling Methods and the Data Generated by
Large-Scale Epigenomic Projects............................................................................142
2.1 Epigenomic Profiling Methods.........................................................................144
3 Current Tools and Analyses That Can Extend Our Insights into Epigenetic
Aberrations in Cancer..............................................................................................149
3.1 Epigenome-Wide Association Studies..............................................................149
3.2 Differential Epigenomic Signals Beyond EWAS..............................................150
3.3 Annotating the Genome Through Epigenomic Profiling..................................152
3.4 Interpretation of Genomic and Epigenomic Variability Through
Enrichment Analyses.........................................................................................154
3.5 Sample Clustering and Classification................................................................155
3.6 Use Cases Illustrating Types of Epigenomic Analyses.....................................156
4 Conclusion................................................................................................................163
References................................................................................................................163
PART 2 EPIGENETICS AND CANCER_
CHAPTER 8 Development of Epigenetic Targeted Therapies in Hematological
Malignancies: From Serendipity to Synthetic Lethality................169
Thomas Prebet and Steven D. Gore
1 Introduction..............................................................................................................170
2 The Methylome in Hematologic Malignancy..........................................................170
2.1 Myelodysplastic Syndrome...............................................................................170
2.2 Acute Myeloid Leukemia..................................................................................171
3 Hypomethylating Agents: The Strange But True History of the Early
Development of Azanucleosides in MDS................................................................171
Contents ix
4 Azacitidine: The Birth of Epigenetic Therapies...................................................172
5 Is There a Correlation Between Methylation and Response to
Hypomethylating Agents?........................................................................................174
6 What Is the Optimal Dosing Regimen?...................................................................175
7 HDAC Inhibitors......................................................................................................176
7.1 HDAC Inhibitors for AML and MDS: A Dead End?........................................176
7.2 Combinations Approaches Based on HDACi Excluding Combination with
Hypomethylating Agents...................................................................................177
7.3 HDAC Inhibitors for Lymphoid Malignancies..................................................177
8 Combination Therapies............................................................................................178
8.1 Aza/HDAC Combinations.................................................................................178
8.2 Other Azanucleoside Combinations..................................................................180
9 Azanucleosides as Immunomodulators....................................................................180
10 Targeted Therapeutics with Major Epigenetic Impact: The Next Generation.........180
11 Conclusion................................................................................................................181
References................................................................................................................182
9 Epigenetic Therapy in Lung Cancer and Mesothelioma................189
Anne-Marie Baird, Derek Richard, Kenneth J. O Byrne, and Steven G. Gray
1 Introduction..............................................................................................................190
2 Overview of Lung Cancer........................................................................................190
3 Lung Cancer as an Epigenetic Disease....................................................................191
3.1 DNA Methy ltransferases...................................................................................193
3.2 Lysine Methyltransferases.................................................................................194
3.3 Lysine Acetyltransferases..................................................................................194
3.4 Lysine Demethylases.........................................................................................195
4 Additional Epigenetic Regulatory Proteins..............................................................195
4.1 Histone Deacetylases........................................................................................196
4.2 Other Histone Marks.........................................................................................196
4.3 miRNA and IncRNA in Lung Cancer...............................................................196
4.4 Smoking Can Also Affect the Lung Epi-Genome.............................................197
5 Epigenetic Targeting of Lung Cancer......................................................................197
5.1 Histone Deacetylase Inhibitors.........................................................................197
5.2 DNA Methyltransferase Inhibitors....................................................................199
5.3 Combination of HDAC and DNMT Inhibitors.................................................200
6 Overview of Malignant Pleural Mesothelioma........................................................201
7 Malignant Pleural Mesothelioma as an Epigenetic Disease....................................201
7.1 miRNAs and IncRNAs in Mesothelioma..........................................................202
8 Epigenetic Targeting in Malignant Pleural Mesothelioma.......................................203
9 Conclusion................................................................................................................205
References................................................................................................................206
x Contents
CHAPTER 10 Breast Cancer Epigenetics........................................................215
Chara A. Pitta and Andreas I. Constantinou
1 Introduction..............................................................................................................215
2 DNA Methylation and Breast Cancer......................................................................216
3 The Role of Histone Deacetylases in Breast Cancer................................................218
4 Histone Modifications..............................................................................................219
5 The Role of microRNAs in Breast Cancer...............................................................220
6 Breast Cancer Epigenetic Treatment........................................................................222
6.1 DNMTs and HDACs Inhibitors.........................................................................222
6.2 Nutrition and Breast Cancer Epigenetics..........................................................224
7 Conclusion................................................................................................................225
Acknowledgment.....................................................................................................226
References................................................................................................................226
CHAPTER 11 Therapeutic Applications of the Prostate Cancer
Epigenome...............................................................................233
Antoinette Sabrina Perry
1 Introduction to Prostate Cancer................................................................................233
1.1 Clinical Management and Treatment of Prostate Cancer..................................234
2 A Snapshot of the Prostate Cancer Epigenome........................................................235
2.1 The Prostate Cancer Methylome.......................................................................235
2.2 Histone Modifications, Variants, and Epigenetic Enzymes in
Prostate Cancer..................................................................................................238
2.3 Noncoding RNAs in Prostate Cancer................................................................240
3 Epigenetic Influences on the Androgen Signaling Axis...........................................240
3.1 Acetylation........................................................................................................242
3.2 Methylation.......................................................................................................243
4 Drugging the Methylome for the Treatment of CRPC.............................................243
4.1 New Classes of DNMT Inhibitors.....................................................................252
5 HDAC Inhibitors for the Treatment of CRPC..........................................................252
5.1 Synergistic Activity...........................................................................................253
6 Targeting AR Signaling by Epigenetic Drugs..........................................................253
7 Chemoprevention and Neutraceutical Therapies.....................................................254
7.1 Isothiocyanates..................................................................................................254
7.2 Curcumin...........................................................................................................255
7.3 Phytoestrogens..................................................................................................255
8 Future Directions......................................................................................................258
Acknowledgments....................................................................................................259
References................................................................................................................259
Contents xi
chapter 12 Liver Cancer (Hepatocellular Carcinoma)...................................269
Shane O Grady and Matthew W. Lawless
1 Liver Cancer: Epidemiology and Risk Factors........................................................269
2 Current Treatment of HCC.......................................................................................270
3 Epigenetics...............................................................................................................272
4 Histone Modification................................................................................................272
5 Characterization of Classic HDACs.........................................................................274
6 HDACS and Cancer.................................................................................................274
7 HDAC Inhibitors......................................................................................................275
8 Anticancer Effects of HDAC Inhibitors...................................................................275
8.1 Apoptosis...........................................................................................................275
8.2 Cell Cycle Arrest...............................................................................................276
8.3 Angiogenesis.....................................................................................................276
9 Endoplasmic Reticulum Stress.................................................................................276
10 ER Stress and Cancer...............................................................................................277
11 ER Stress and HDACs..............................................................................................277
12 HDAC Inhibitors in Treatment of HCC...................................................................279
13 DNA Methylation in HCC.......................................................................................281
14 Other Epigenetic Regulatory Proteins......................................................................281
15 ncRNAs....................................................................................................................281
16 Conclusion................................................................................................................282
References................................................................................................................282
CHAPTER 13 Neuroblastoma.........................................................................289
Olga Piskareva and Raymond L. Stallings
1 Neuroblastoma.........................................................................................................290
2 Epigenetic Changes..................................................................................................291
2.1 DNA Methylation..............................................................................................291
2.2 Histone Modifications.......................................................................................292
2.3 Histone Deacetylase Expression.......................................................................293
2.4 miRNA..............................................................................................................298
2.5 Long Noncoding RNAs.....................................................................................305
3 Epigenetic Targeting Agents....................................................................................306
3.1 DNA Methylation Inhibitor...............................................................................306
3.2 Inhibitors of Histone Modification Enzymes....................................................306
3.3 Differentiation Therapeutics.............................................................................307
4 miRNA-Based Therapeutics.....................................................................................308
4.1 miRNA Replacement Therapy..........................................................................308
4.2 miRNA Knockdown Therapy............................................................................310
References................................................................................................................311
xii Contents
CHAPTER 14 The Epigenetics of Medulloblastoma..........................................317
Clara Penas, Vasileios Stathias, Bryce K. Allen, and Nagi G. Ayad
1 Introduction..............................................................................................................317
2 Medulloblastoma Subtypes......................................................................................318
3 Epigenetic Enzymes HDACs and HATs as Targets in Medulloblastoma................319
4 HDAC Inhibitors as Medulloblastoma Therapeutics...............................................321
5 Methyltransferases in Medulloblastoma..................................................................323
6 Epigenetic Readers in Medulloblastoma..................................................................324
7 Established Kinases May Also Be Epigenetic Regulators in
Medulloblastoma......................................................................................................325
8 The Intersection of the Ubiquitin Proteasome Pathway and the Epigenetic
Pathway in Medulloblastoma...................................................................................326
9 MicroRNAs as Medulloblastoma Targets................................................................327
10 Drug Discovery Considerations in Medulloblastoma..............................................329
11 Conclusions..............................................................................................................331
Acknowledgments....................................................................................................332
References................................................................................................................332
CHAPTER 15 Clinical Significance of Epigenetic Alterations in
Glioblastoma............................................................................339
Fumiharu Ohka, Atsushi Natsume, and Yutaka Kondo
1 Introduction..............................................................................................................339
2 Intertumoral and Intratumoral Heterogeneity of GBM............................................341
3 Aberrant DNA Methylation in GBM.......................................................................341
4 Aberrant Histone Modifications and Chromatin Remodeling in GBM...................342
5 Contribution of GSC to GBM Formation and Progression......................................344
6 Mechanism of Establishment of H3K27me3 Landscape During GSC
Differentiation..........................................................................................................345
7 Novel Treatment Strategy for GBM.........................................................................345
Acknowledgments....................................................................................................347
References................................................................................................................347
CHAPTER 16 Esophageal Cancer...................................................................351
Zhe Jin, Xiaojing Zhang, and Xinmin Fan
1 Introduction..............................................................................................................351
2 DNA Methylation.....................................................................................................353
2.1 Hypermethylated Genes in BE and EAC..........................................................353
2.2 Hypermethylated Genes in ESCC.....................................................................355
2.3 TSG Hypermethylation as Biomarker in Esophageal Cancer...........................356
3 Dysregulation of miRNA.........................................................................................359
Contents xiii
3.1 miRNAs Profiling and Their Target Genes in Esophageal Cancer...................359
3.2 miRNA as Biomarker in Esophageal Cancer....................................................362
4 Opportunities to Epigenetically Target Esophageal Cancer.....................................364
5 Other Epigenetic Events in Esophageal Cancer.......................................................365
5.1 Histone Acetylases/Deacetylases and Histone Methyltransferases/
Demethylases....................................................................................................365
5.2 Long Noncoding RNA......................................................................................366
References................................................................................................................367
CHAPTER 17 Nasopharyngeal Cancer............................................................373
Li-Xia Peng and Chao-Nan Qian
1 Introduction..............................................................................................................373
2 DNA Hypermethylation in NPC..............................................................................374
3 Histone Modifications in NPC.................................................................................377
4 MicroRNA Alterations in NPC................................................................................378
5 Long Noncoding RNAs in NPC...............................................................................378
6 Clinical Trials...........................................................................................................378
7 Future Perspectives..................................................................................................380
References................................................................................................................381
PART 3 TARGETING ABERRANT EPIGENETICS_
CHAPTER 18 Nutritional Epigenetic Regulators in the Field of Cancer:
New Avenues for Chemopreventive Approaches..........................393
Michael Schnekenburger and Marc Diederich
1 Introduction..............................................................................................................394
2 Overview of the Cancer Epigenome........................................................................395
2.1 Histone Modifications.......................................................................................395
2.2 DNA Methylation..............................................................................................397
2.3 Epigenetic Readers............................................................................................397
2.4 MicroRNAs.......................................................................................................398
3 Dietary Factors and Their Influence on Epigenetics: Avenue for Dietary
Intervention to Prevent Cancer.................................................................................399
3.1 Modulation of Epigenetic Cofactors by Nutrients and Metabolism.................400
3.2 Other Diet-Derived Nutrients Affecting Epigenetic Mechanisms....................406
3.3 Phytochemicals Targeting Epigenetic Enzymes................................................407
4 Conclusions and Critical Considerations.................................................................416
Acknowledgments....................................................................................................418
References................................................................................................................418
xiv Contents
CHAPTER 19 Emerging Epigenetic Therapies—Lysine Methyltransferase/PRC
Complex Inhibitors....................................................................427
Vineet Pande, David J. Pocalyko, and Dashyant Dhanak
1 Introduction..............................................................................................................427
2 PRC2 Structure-Function and Drugability..............................................................428
3 Role of PRC2 in Cancer and EZH2 as a Drug Target..............................................429
4 Discovery of Inhibitors of EZH2/PRC2...................................................................430
5 Conclusions..............................................................................................................434
References................................................................................................................435
CHAPTER 20 Inhibitors of Jumonji C-Domain Histone Demethylases.................439
Peter Staller
1 Introduction: Histone Methylation—Normal and Pathological Functions..............439
2 The First Histone Demethylases: LSD1 and LSD2.................................................441
3 The Jumonji C-Domain Histone Demethylases.......................................................442
4 Role of JMJC Histone Demethylases in Human Cancer.........................................444
5 Small Compound Inhibitors of JMJC Histone Demethylases..................................451
6 Conclusion................................................................................................................457
References................................................................................................................459
CHAPTER 21 Emerging Epigenetic Therapies: Lysine Acetyltransferase
Inhibitors.................................................................................471
Stephanie Kaypee, Somnath Mandal, Snehajyoti Chatterjee, and Tapas K. Kundu
1 Introduction..............................................................................................................471
2 Aberrant Histone Acetylation Patterns in Diseases..................................................473
3 Role of KATs in Cancer...........................................................................................475
3.1 p300/CBP Family..............................................................................................475
3.2 GNAT Family....................................................................................................476
3.3 MYST Family...................................................................................................477
4 Lysine Acetyltransferases as Potential Therapeutic Targets.....................................479
4.1 Bisubstrate Inhibitors........................................................................................479
4.2 KAT Inhibitors: Natural Products.....................................................................482
4.3 KAT Inhibitors: Synthetic Derivatives and Analogs of Natural Products.........484
4.4 KAT Inhibitors: Synthetic Small Molecules.....................................................485
5 Conclusion and Perspective.....................................................................................486
References................................................................................................................486
CHAPTER 22 Emerging Epigenetic Therapies—Bromodomain Ligands.............495
David S. Hewings, Timothy PC. Rooney, and Stuart J. Conway
1 Introduction..............................................................................................................496
1.1 Bromodomains—a KAc Recognition Domain.................................................496
Contents
xv
1.2 Classification of Human Bromodomains..........................................................498
1.3 Functions of BET bromodomains.....................................................................498
1.4 The roles of BET BCPs in cancer.....................................................................500
2 The Development of BET Bromodomain Ligands..................................................501
2.1 Diazepine-Based BET Bromodomain Ligands.................................................501
2.2 3,5-Dimethylisoxazole-Based Bromodomain Ligands.....................................502
2.3 RVX-208 (5)......................................................................................................505
2.4 PFI-1 (10)..........................................................................................................506
2.5 Thiazol-2-One-Based Bromodomain Ligands..................................................506
2.6 Diazobenzene-Based Bromodomain Ligands...................................................506
2.7 4-Acylpyrroles—XD14 (14).............................................................................507
2.8 I-BET726 (GSK1324726A, 12)........................................................................507
2.9 In Silico Approaches to the Discovery of BET Bromodomain-Binding
Fragments.................................................................................................................507
2.10 Dual kinase-bromodomain inhibitors..............................................................508
3 BET Bromodomain Ligands in Clinical Trials........................................................509
3.1 BET Bromodomain Ligands and Cancer..........................................................510
3.2 BET Bromodomain Ligands and Inflammation................................................511
3.3 BET Bromodomain Ligands in Clinical Trials.................................................511
4 The Development of CREBBP Bromodomain Ligands..........................................513
4.1 N-Acety lated fragments....................................................................................513
4.2 Azobenzene-Based CREBBP Bromodomain Ligands......................................513
4.3 A CREBBP Bromodomain-Binding Cyclic Peptide.........................................513
4.4 Dihydroquinoxalinone-Based CREBBP Bromodomain Ligands.....................514
4.5 3,5-Dimethylisoxazole-Based CREBBP Bromodomain Ligands.....................514
5 The Development of Ligands for Other Bromodomains.........................................515
6 Conclusion................................................................................................................517
References................................................................................................................517
CHAPTER 23 Clinical Trials...........................................................................525
Wei Zhu and Jiaqi Qian
1 Introduction..............................................................................................................525
2 Single Agent Therapy...............................................................................................526
2.1 DNA Methyltransferase Inhibitors....................................................................526
2.2 Histone Deacetylase Inhibitors.........................................................................557
2.3 Histone Acetylation Transferase (HAT) Inhibitors...........................................559
3 Combination Therapy...............................................................................................560
3.1 In Combination with Other Oncology Drugs....................................................560
3.2 In Combination with Other Epigenetic Agents.................................................561
4 Conclusion and Future Perspectives........................................................................562
References................................................................................................................563
xvi Contents
PART 4 ISSUES TO OVERCOME/AREAS OF CONCERN_
CHAPTER 24 Genetic Intratumor Heterogeneity..............................................571
DonatAlpar, Louise J. Barber, and Marco Gerlinger
1 Introduction: Inter- and Intratumor Heterogeneity...................................................571
2 Genetic ITH as a Result of Population Expansion...................................................572
3 Cancer from an Evolutionary Perspective................................................................573
4 Patterns of ITH.........................................................................................................576
4.1 ITH in Solid Tumors.........................................................................................576
4.2 ITH in Leukemias.............................................................................................581
5 ITH and the Evolution of Drug Resistance..............................................................582
6 Clinical Implications of ITH....................................................................................587
Acknowledgments....................................................................................................587
References................................................................................................................587
CHAPTER 25 Epigenetics Underpinning DNA Damage Repair...........................595
Derek J. Richard, Emma Bolderson, Anne-Marie Baird, and Kenneth
J. 0 Byrne
1 Introduction..............................................................................................................595
2 Epigenetic Changes in Chromatin............................................................................596
2.1 Histone Modifications.......................................................................................596
2.2 DNA Methylation..............................................................................................597
2.3 MicroRNAs.......................................................................................................597
3 DNA Damage...........................................................................................................597
4 DNA Repair Pathways.............................................................................................598
4.1 Mismatch Repair...............................................................................................598
4.2 Base Excision Repair........................................................................................598
4.3 Nucleotide Excision Repair...............................................................................599
4.4 Double-Strand Break Repair.............................................................................599
5 Epigenetic Modifications of Double-Strand Break Repair......................................600
5.1 DNA Repair-Induced Histone Modifications....................................................600
5.2 Phosphorylation.................................................................................................600
5.3 Ubiquitination...................................................................................................601
5.4 Methylation.......................................................................................................602
5.5 Acetylation and Deacetylation..........................................................................602
6 Chromatin Remodeling Factors Recruited to Sites of DNA Damage......................603
7 DNA Repair in Heterochromatin.............................................................................604
8 Conclusion................................................................................................................605
References................................................................................................................605
Contents xvii
CHAPTER 26 Epigenetics of Cisplatin Resistance...........................................613
Steven G. Gray
1 Introduction..............................................................................................................614
2 DNA Methylation........................................................................¦.............................614
2.1 DNA Methylation Changes Associated with Cisplatin Resistance...................614
2.2 Methylation in Cancer Cell Lines May Not Truly Reflect the
Methylation from the Primary Tumor......................................................................615
3 Epigenetic Readers, Writers, and Erasers................................................................616
3.1 Lysine Acetyltransferases..................................................................................616
3.2 Tip60/Kat5—A Master Regulator of Cisplatin Resistance...............................617
3.3 EZH2/PRC2 Complexes and Cisplatin Resistance...........................................617
3.4 Epigenetic Erasers Associated with Cisplatin Resistance.................................617
3.5 Epigenetic Readers Associated with Cisplatin Resistance................................618
3.6 BRCA1 Complexes Containing Epigenetic ReadersAVriters and Erasers as a
Critical Element in Cisplatin Resistance..................................................................618
4 Noncoding RNAs.....................................................................................................621
4.1 miRNAs Associated with Cisplatin Resistance/Sensitivity...............................621
4.2 epi-miRNAs and Cisplatin Sensitivity..............................................................622
4.3 IncRNAs Associated with Resistance/Sensitivity.............................................622
5 Histone Variants.......................................................................................................623
6 Cancer Stem Cells and Cisplatin Resistance............................................................623
7 Protein PTMs Associated with Development of Cisplatin Resistance.....................624
8 Targeting Cisplatin Resistance Epigenetically.........................................................625
8.1 Natural Bioactives.............................................................................................625
9 Clinical Trials...........................................................................................................626
9.1 Low Dose Therapies as Epigenetic Priming Events......................................628
10 Conclusion................................................................................................................629
References................................................................................................................629
CHAPTER 27 Therapeutically Targeting Epigenetic Regulation of Cancer
Stem Cells................................................................................639
Brendan Ffrench, John J. O Leary, and Michael F. Gallagher
1 Principles of Stem Cell Biology...............................................................................640
1.1 Introduction.......................................................................................................640
1.2 Potency..............................................................................................................640
1.3 Maintenance of the SR State.............................................................................640
1.4 Asymmetric Division and Differentiation.........................................................642
1.5 Establishment, Growth, and Repair of Tissues.................................................643
1.6 SC Populations Are Organized as Stem-Progenitor Cell Hierarchies..............644
1.7 SC Properties and Regulation of Cell Cycle Exit.............................................645
xviii Contents
2 Cancer and Cancer Stem Cells.................................................................................645
2.1 Introduction.......................................................................................................645
2.2 Development of CSC Theory............................................................................646
2.3 Defining Principles of CSC Theory..................................................................646
2.4 CSCs and Tumor Development.........................................................................647
3 Epigenetic Regulation of CSC SR and Differentiation............................................648
3.1 Introduction.......................................................................................................648
3.2 Regulation of Pluripotency by Oct4, Sox2, and Nanog....................................648
3.3 Epigenetic Regulation of SCs and CSCs by Sternness Signaling Pathways.....649
3.4 Sternness Signaling Pathways and Epigenetic Regulation by miRNAs
and DNA Remodeling..............................................................................................649
3.5 Wnt/p-Catenin Signaling...................................................................................650
3.6 Hedgehog Signaling..........................................................................................651
3.7 Notch Signaling.................................................................................................652
3.8 TGF-p Signaling................................................................................................653
4 Therapeutic Targeting of CSCs................................................................................654
4.1 Introduction.......................................................................................................654
4.2 Challenges for CSC Therapeutics.....................................................................654
4.3 Targeting CSCs via Forced Differentiation.......................................................655
4.4 Targeting CSCs via Wnt Signaling....................................................................655
4.5 Targeting CSCs via Hedgehog Signaling..........................................................655
4.6 Targeting CSCs via Notch Signaling.................................................................656
4.7 Targeting CSCs via TGF-p Signaling................................................................656
4.8 Targeting CSCs via PRC2 Component EZH2...................................................657
4.9 Targeting CSCs via miRNA Mechanisms.........................................................657
5 Perspective: CSCs and the Future of Cancer Therapeutics......................................658
5.1 Epigenetic CSC Signatures as Biomarkers.......................................................658
5.2 Fighting Fire with Fire: Awakening CSCs for Enhanced Chemoresponse.......658
5.3 Zero-Collateral CSC Targeting.........................................................................659
References................................................................................................................659
PART 5 FUTURE DIRECTIONS: TRANSLATION TO THE CLINIC_
CHAPTER 28 Personalized Epigenetic Therapy—Chemosensitivity Testing.......667
Benet Pera and Leandro Cerchietti
1 Introduction..............................................................................................................667
2 Chemoresistance in Lymphomas..............................................................................668
3 Epigenetically Encoded Chemoresistance...............................................................668
4 Implementing Epigenetic Therapy to Chemosensitize Lymphoma.........................669
5 What Antitumoral Effect to Expect from Epigenetic Drugs?..................................670
Contents xix
6 Selecting the Right Drug for the Right Patient and Vice Versa................................670
6.1 Cellular Reprogramming...................................................................................671
6.2 Synthetic Lethality............................................................................................671
7 Resistance to Epigenetic-Acting Drugs and Chemosensitivity Testing...................674
8 Conclusion................................................................................................................674
References................................................................................................................675
CHAPTER 29 Personalized Therapy—Epigenetic Profiling as Predictors
of Prognosis and Response.......................................................677
Holger Heyn
1 Epigenetic Biomarkers for Precision Medicine.......................................................677
2 Systems Epigenomics for Biomarker Discovery.....................................................680
2.1 Functional Epigenetic Alterations.....................................................................681
2.2 Epigenetic Surrogate Biomarker.......................................................................681
3 Epigenetic Biomarkers for Diagnosis, Prognosis, and Drug Response...................682
3.1 Diagnostic Epigenetic Biomarkers....................................................................682
3.2 Prognostic Epigenetic Biomarkers....................................................................684
3.3 Biomarker Guiding Therapeutic Decision........................................................685
4 Genetic Alterations in Epigenetic Modifiers: Potential Drug Targets......................688
4.1 Epigenetic Drugs in Clinical Use and Trials.....................................................688
4.2 Application of Epigenetic Therapeutics in a Noncancer Context.....................690
4.3 A New Generation of Targeted Epigenetic Drugs.............................................691
5 Future Perspective of Biomarker Discovery and Application..................................692
References................................................................................................................692
Index...................................................................................................................................................699
|
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| id | DE-604.BV043189326 |
| illustrated | Illustrated |
| indexdate | 2024-07-10T07:20:06Z |
| institution | BVB |
| isbn | 9780128002063 |
| language | English |
| oai_aleph_id | oai:aleph.bib-bvb.de:BVB01-028613016 |
| oclc_num | 915351617 |
| open_access_boolean | |
| owner | DE-19 DE-BY-UBM |
| owner_facet | DE-19 DE-BY-UBM |
| physical | XXVI, 721 S. Ill., graph. Darst. 23 cm |
| publishDate | 2015 |
| publishDateSearch | 2015 |
| publishDateSort | 2015 |
| publisher | Academic Press |
| record_format | marc |
| series2 | Translational epigenetics series |
| spelling | Epigenetic cancer therapy edited by Steven G. Gray Amsterdam ; Heidelberg [u.a.] Academic Press 2015 XXVI, 721 S. Ill., graph. Darst. 23 cm txt rdacontent n rdamedia nc rdacarrier Translational epigenetics series Therapie (DE-588)4059798-2 gnd rswk-swf Krebs Medizin (DE-588)4073781-0 gnd rswk-swf Epigenetik (DE-588)7566079-9 gnd rswk-swf Krebs Medizin (DE-588)4073781-0 s Therapie (DE-588)4059798-2 s Epigenetik (DE-588)7566079-9 s DE-604 Gray, Steven edt HBZ Datenaustausch application/pdf http://bvbr.bib-bvb.de:8991/F?func=service&doc_library=BVB01&local_base=BVB01&doc_number=028613016&sequence=000002&line_number=0001&func_code=DB_RECORDS&service_type=MEDIA Inhaltsverzeichnis |
| spellingShingle | Epigenetic cancer therapy Therapie (DE-588)4059798-2 gnd Krebs Medizin (DE-588)4073781-0 gnd Epigenetik (DE-588)7566079-9 gnd |
| subject_GND | (DE-588)4059798-2 (DE-588)4073781-0 (DE-588)7566079-9 |
| title | Epigenetic cancer therapy |
| title_auth | Epigenetic cancer therapy |
| title_exact_search | Epigenetic cancer therapy |
| title_full | Epigenetic cancer therapy edited by Steven G. Gray |
| title_fullStr | Epigenetic cancer therapy edited by Steven G. Gray |
| title_full_unstemmed | Epigenetic cancer therapy edited by Steven G. Gray |
| title_short | Epigenetic cancer therapy |
| title_sort | epigenetic cancer therapy |
| topic | Therapie (DE-588)4059798-2 gnd Krebs Medizin (DE-588)4073781-0 gnd Epigenetik (DE-588)7566079-9 gnd |
| topic_facet | Therapie Krebs Medizin Epigenetik |
| url | http://bvbr.bib-bvb.de:8991/F?func=service&doc_library=BVB01&local_base=BVB01&doc_number=028613016&sequence=000002&line_number=0001&func_code=DB_RECORDS&service_type=MEDIA |
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