Epigenetic Cancer Therapy

 
 
Academic Press
  • 1. Auflage
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  • erschienen am 1. Juli 2015
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  • 748 Seiten
 
E-Book | ePUB mit Adobe DRM | Systemvoraussetzungen
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E-Book | ePUB mit Adobe DRM | Systemvoraussetzungen
978-0-12-800224-7 (ISBN)
 

Epigenetic Cancer Therapy unites issues central to a translational audience actively seeking to understand the topic. It is ideal for cancer specialists, including oncologists and clinicians, but also provides valuable information for researchers, academics, students, governments, and decision-makers in the healthcare sector.

The text covers the basic background of the epigenome, aberrant epigenetics, and its potential as a target for cancer therapy, and includes individual chapters on the state of epigenome knowledge in specific cancers (including lung, breast, prostate, liver).

The book encompasses both large-scale intergovernmental initiatives as well as recent findings across cancer stem cells, rational drug design, clinical trials, and chemopreventative strategies. As a whole, the work articulates and raises the profile of epigenetics as a therapeutic option in the future management of cancer.


  • Concisely summarizes the therapeutic implications of recent, large-scale epigenome studies, including the cancer epigenome atlas
  • Discusses targeted isoform specific versus pan-specific inhibitors, a rational drug design approach to epigenetics relevant to pharmacoepigenetic clinical applications
  • Covers new findings in the interplay between cancer stem cells (CSCs) and drug resistance, demonstrating that epigenetic machinery is a candidate target for the eradication of these CSCs
  • Englisch
  • USA
Elsevier Science
  • 17,67 MB
978-0-12-800224-7 (9780128002247)
0128002247 (0128002247)
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  • Front Cover
  • Epigenetic Cancer Therapy
  • Copyright Page
  • Contents
  • List of Contributors
  • 1 Introduction
  • 1 Introduction to the Area (Key Concepts)
  • 2 Epigenetics and Cancer
  • 3 Targeting Aberrant Epigenetics
  • 4 Issues to Overcome/Areas of Concern
  • 5 Future Directions: Translation to the Clinic
  • References
  • 1 Introduction and Key Concepts
  • 2 DNA Methylation and Hydroxymethylation in Cancer
  • 1 Introduction
  • 2 Epigenetics
  • 2.1 Chromatin Structure
  • 2.2 DNA Methylation in Cellular Homeostasis
  • 2.2.1 Genomic distribution of DNA methylation
  • 2.2.2 Functional role of DNA methylation
  • 2.2.3 DNA methyltransferases
  • 2.2.4 Recruitment of DNMTs
  • 2.3 DNA Demethylation
  • 3 DNA Methylation Patterns in Cancer
  • 3.1 Hypermethylation in Cancer
  • 3.2 Hypomethylation in Cancer
  • 3.3 Methods for 5mC Detection
  • 4 Aberrations of Enzymes Involved in DNA Methylation Homeostasis in Cancer
  • 4.1 DNA Methyltransferase
  • 4.2 TET Proteins
  • 4.3 Isocitrate Dehydrogenases
  • 4.4 Succinate Dehydrogenases
  • 5 DNA Hydroxymethylation in Cancer
  • 5.1 Methods for 5hmC Detection
  • 5.1.1 Affinity-based enrichment approach
  • 5.1.2 Chemical methods
  • 5.1.3 Quantitative methods at single base resolution
  • 5.1.4 Third-generation sequencing
  • 5.2 DNA Hydroxymethylation Patterns in Cancer
  • 6 Conclusion
  • References
  • 3 Writers, Readers, and Erasers of Epigenetic Marks
  • 1 Introduction
  • 2 Writers
  • 2.1 DNA Methyltransferases
  • 2.2 Histone Lysine Methyltransferases
  • 2.3 Protein Arginine Methyltransferases
  • 2.4 Histone Acetyltransferases
  • 3 Readers
  • 3.1 Methyl-CpG-Binding Proteins
  • 3.2 Histone Methylation-Binding Domains
  • 3.3 Histone Acetylation-Binding Domains
  • 4 Erasers
  • 4.1 Proteins Involved in DNA Demethylation
  • 4.2 Histone Demethylases
  • 4.3 Histone Deacetylases (HDACs)
  • 5 Interactions between the Various Components
  • 6 Epigenetics and Cancer
  • 6.1 DNA Methylation and Cancer
  • 6.2 Histone Methylation and Cancer
  • 6.3 Histone Acetylation and Cancer
  • 7 Epigenetic Proteins as Therapeutic Targets
  • 8 Conclusion and Future Opportunities
  • References
  • 4 MicroRNAs and Cancer
  • 1 miRNA Biogenesis and Functionality
  • 2 miRNAs in Cancer Biology
  • 3 miRNA: An Epigenetic Perspective
  • 3.1 Epigenetic Alteration of miRNA Expression
  • 3.2 Epi-miRNA
  • 3.3 miRNA with Epigenetic Functions
  • 4 miRNA Epigenetic Therapy
  • 4.1 miRNA Inhibition in Cancer
  • 4.2 miRNA Replacement in Cancer
  • 4.3 Small-Molecule-Based miRNA Modulation
  • 5 Future Perspectives
  • Acknowledgments
  • References
  • 5 Long Noncoding RNAs and Cancer
  • 1 Introduction
  • 2 Classification and Nomenclature of lncRNAs
  • 2.1 Classification
  • 2.2 Nomenclature
  • 3 Mechanisms of lncRNA Function
  • 3.1 lncRNAs as Decoys and Guides
  • 3.2 lncRNAs as Scaffolds
  • 3.3 lncRNAs as Signaling Molecules
  • 3.4 miRNA Sequestration
  • 3.5 lncRNAs and Epigenetic Regulation
  • 3.5.1 H19
  • 3.5.2 AIR and KCNQ1OT1
  • 3.5.3 lincRNAs
  • 4 lncRNAs and Human Disease
  • 4.1 Prognostic Markers
  • 4.1.1 lncRNAs in the circulation
  • 4.1.2 Prostate cancer antigen 3 (nonprotein coding)
  • 4.1.3 MALAT1
  • 4.1.4 Highly upregulated in liver cancer
  • 5 Methods for Studying lncRNA Expression
  • 5.1 High-Throughput Analysis for Discovery
  • 5.1.1 Microarrays
  • 5.1.2 Transcriptome analysis
  • 5.1.3 Computational prediction
  • 5.2 Verification of Single Candidates Identified from High-Throughput Data
  • 5.2.1 Northern blots and RT-qPCR
  • 5.2.2 Fluorescence in situ hybridization
  • 5.3 Studying the Interactions Between lncRNAs and Protein
  • 5.3.1 RNA immunoprecipitation
  • 6 Strategies for Manipulating lncRNA Expression
  • 6.1 Oligonucleotide-Based Methods
  • 6.2 RNA Interference
  • 6.3 Targeting lncRNAs with Natural Antisense Transcripts
  • 6.4 Targeting lncRNAs with Small Molecule Inhibitors
  • 7 Conclusions
  • References
  • 6 Ribosomal RNA Methylation and Cancer
  • 1 Introduction
  • 2 Overview of Human Ribosome Biogenesis: An Intense Energy Consuming Process
  • 3 Transcriptional and Epigenetic Deregulation of rDNA Gene Expression in Cancer
  • 3.1 Organization of rDNA Genes and Their Transcription
  • 3.2 Targeting rDNA Transcription for Anticancer Drug Development
  • 4 Chemical Modifications of rRNA
  • 4.1 The rRNA Pseudouridylation Machinery
  • 4.2 The rRNA 2´-O-Methylation Machinery
  • 5 Function of rRNA Methylation
  • 5.1 The Complex Functional Architecture of the Ribosome
  • 5.2 Regulatory Role of rRNA Methylation: An Emerging Concept
  • 6 Modification of rRNA Methylation in Cancer
  • 6.1 Alterations of snoRNA Expression in Cancer
  • 6.2 Deregulation of Gene Expression Coding for rRNA Methylation Complex Proteins
  • 7 Concluding Remarks
  • References
  • 7 Mining the Epigenetic Landscape: Surface Mining or Deep Underground
  • 1 Introduction
  • 2 Summary of Epigenomic Profiling Methods and the Data Generated by Large-Scale Epigenomic Projects
  • 2.1 Epigenomic Profiling Methods
  • 2.1.1 DNA methylation
  • 2.1.2 Alternative histones and histone modifications
  • 2.1.3 Chromatin accessibility
  • 2.1.4 Gene expression
  • 2.1.5 Chromatin conformation
  • 2.1.6 Epigenomic projects and publicly available epigenomic data
  • 3 Current Tools and Analyses That Can Extend Our Insights into Epigenetic Aberrations in Cancer
  • 3.1 Epigenome-Wide Association Studies
  • 3.2 Differential Epigenomic Signals Beyond EWAS
  • 3.3 Annotating the Genome Through Epigenomic Profiling
  • 3.4 Interpretation of Genomic and Epigenomic Variability Through Enrichment Analyses
  • 3.5 Sample Clustering and Classification
  • 3.6 Use Cases Illustrating Types of Epigenomic Analyses
  • 3.6.1 Use Case-Inferring the Most Likely Cell Type of Origin for Breast Cancer Cell Lines
  • 3.6.2 Use Case-Comparing Methylation Profile of Normal Breast and Breast Cancer Samples Against Immune Cell Reference Epige ...
  • 3.6.3 Use Case-Studying Epigenomic Aberrations in Promyelocytic Leukemia to Determine Biological Pathways That Are Affected
  • 3.6.4 Use Case-Interpreting Genomic Variation in the Context of Global Chromatin State Patterns
  • 4 Conclusion
  • References
  • 2 Epigenetics and Cancer
  • 8 Development of Epigenetic Targeted Therapies in Hematological Malignancies: From Serendipity to Synthetic Lethality
  • 1 Introduction
  • 2 The Methylome in Hematologic Malignancy
  • 2.1 Myelodysplastic Syndrome
  • 2.2 Acute Myeloid Leukemia
  • 3 Hypomethylating Agents: The Strange But True History of the Early Development of Azanucleosides in MDS
  • 4 Azacitidine: The Birth of "Epigenetic" Therapies
  • 5 Is There a Correlation Between Methylation and Response to Hypomethylating Agents?
  • 6 What Is the Optimal Dosing Regimen?
  • 7 HDAC Inhibitors
  • 7.1 HDAC Inhibitors for AML and MDS: A Dead End?
  • 7.2 Combinations Approaches Based on HDACi Excluding Combination with Hypomethylating Agents
  • 7.3 HDAC Inhibitors for Lymphoid Malignancies
  • 8 Combination Therapies
  • 8.1 Aza/HDAC Combinations
  • 8.2 Other Azanucleoside Combinations
  • 9 Azanucleosides as Immunomodulators
  • 10 Targeted Therapeutics with Major Epigenetic Impact: The Next Generation
  • 11 Conclusion
  • References
  • 9 Epigenetic Therapy in Lung Cancer and Mesothelioma
  • 1 Introduction
  • 2 Overview of Lung Cancer
  • 3 Lung Cancer as an Epigenetic Disease
  • 3.1 DNA Methyltransferases
  • 3.2 Lysine Methyltransferases
  • 3.3 Lysine Acetyltransferases
  • 3.4 Lysine Demethylases
  • 4 Additional Epigenetic Regulatory Proteins
  • 4.1 Histone Deacetylases
  • 4.2 Other Histone Marks
  • 4.3 miRNA and lncRNA in Lung Cancer
  • 4.4 Smoking Can Also Affect the Lung Epi-Genome
  • 5 Epigenetic Targeting of Lung Cancer
  • 5.1 Histone Deacetylase Inhibitors
  • 5.2 DNA Methyltransferase Inhibitors
  • 5.3 Combination of HDAC and DNMT Inhibitors
  • 6 Overview of Malignant Pleural Mesothelioma
  • 7 Malignant Pleural Mesothelioma as an Epigenetic Disease
  • 7.1 miRNAs and lncRNAs in Mesothelioma
  • 8 Epigenetic Targeting in Malignant Pleural Mesothelioma
  • 9 Conclusion
  • References
  • 10 Breast Cancer Epigenetics
  • 1 Introduction
  • 2 DNA Methylation and Breast Cancer
  • 3 The Role of Histone Deacetylases in Breast Cancer
  • 4 Histone Modifications
  • 5 The Role of microRNAs in Breast Cancer
  • 6 Breast Cancer Epigenetic Treatment
  • 6.1 DNMTs and HDACs Inhibitors
  • 6.2 Nutrition and Breast Cancer Epigenetics
  • 7 Conclusion
  • Acknowledgment
  • References
  • 11 Therapeutic Applications of the Prostate Cancer Epigenome
  • 1 Introduction to Prostate Cancer
  • 1.1 Clinical Management and Treatment of Prostate Cancer
  • 2 A Snapshot of the PROSTATE CANCER Epigenome
  • 2.1 The PROSTATE CANCER Methylome
  • 2.2 Histone Modifications, Variants, and Epigenetic Enzymes in PROSTATE CANCER
  • 2.3 Noncoding RNAs IN PROSTATE CANCER
  • 3 Epigenetic Influences on the Androgen Signaling Axis
  • 3.1 Acetylation
  • 3.2 Methylation
  • 4 Drugging the Methylome for the Treatment of CRPC
  • 4.1 New Classes of DNMT Inhibitors
  • 5 HDAC Inhibitors for the Treatment of CRPC
  • 5.1 Synergistic Activity
  • 6 Targeting AR Signaling by Epigenetic Drugs
  • 7 Chemoprevention and Neutraceutical Therapies
  • 7.1 Isothiocyanates
  • 7.2 Curcumin
  • 7.3 Phytoestrogens
  • 8 Future Directions
  • Acknowledgments
  • References
  • 12 Liver Cancer (Hepatocellular Carcinoma)
  • 1 Liver Cancer: Epidemiology and Risk Factors
  • 2 Current Treatment of HCC
  • 3 Epigenetics
  • 4 Histone Modification
  • 5 Characterization of Classic HDACs
  • 6 HDACS and Cancer
  • 7 HDAC Inhibitors
  • 8 Anticancer Effects of HDAC Inhibitors
  • 8.1 Apoptosis
  • 8.2 Cell Cycle Arrest
  • 8.3 Angiogenesis
  • 9 Endoplasmic Reticulum Stress
  • 10 ER Stress and Cancer
  • 11 ER Stress and HDACs
  • 12 HDAC Inhibitors in Treatment of HCC
  • 13 DNA Methylation in HCC
  • 14 Other Epigenetic Regulatory Proteins
  • 15 ncRNAs
  • 16 Conclusion
  • References
  • 13 Neuroblastoma
  • 1 Neuroblastoma
  • 2 Epigenetic Changes
  • 2.1 DNA Methylation
  • 2.1.1 Aberrant hypermethylation of CpGs within gene promoters
  • 2.1.2 Genome-wide aberrant hypermethylation of CpGs islands assessment
  • 2.2 Histone Modifications
  • 2.3 Histone Deacetylase Expression
  • 2.4 miRNA
  • 2.4.1 miRNA expression patterns
  • 2.4.2 Individual miRNAs
  • 2.4.3 Epigenetic control of miRNA expression
  • 2.5 Long Noncoding RNAs
  • 2.5.1 Long noncoding RNAs
  • 2.5.2 Epigenetic control of lncRNA expression
  • 3 Epigenetic Targeting Agents
  • 3.1 DNA Methylation Inhibitor
  • 3.2 Inhibitors of Histone Modification Enzymes
  • 3.3 Differentiation Therapeutics
  • 4 miRNA-Based Therapeutics
  • 4.1 miRNA Replacement Therapy
  • 4.2 miRNA Knockdown Therapy
  • References
  • 14 The Epigenetics of Medulloblastoma
  • 1 Introduction
  • 2 Medulloblastoma Subtypes
  • 3 Epigenetic Enzymes HDACs and HATs as Targets in Medulloblastoma
  • 4 HDAC Inhibitors as Medulloblastoma Therapeutics
  • 5 Methyltransferases in Medulloblastoma
  • 6 Epigenetic Readers in Medulloblastoma
  • 7 Established Kinases May Also Be Epigenetic Regulators in Medulloblastoma
  • 8 The Intersection of the Ubiquitin Proteasome Pathway and the Epigenetic Pathway in Medulloblastoma
  • 9 MicroRNAs as Medulloblastoma Targets
  • 10 Drug Discovery Considerations in Medulloblastoma
  • 11 Conclusions
  • Acknowledgments
  • References
  • 15 Clinical Significance of Epigenetic Alterations in Glioblastoma
  • 1 Introduction
  • 2 Intertumoral and Intratumoral Heterogeneity of GBM
  • 3 Aberrant DNA Methylation in GBM
  • 4 Aberrant Histone Modifications and Chromatin Remodeling in GBM
  • 5 Contribution of GSC to GBM Formation and Progression
  • 6 Mechanism of Establishment of H3K27me3 Landscape During GSC Differentiation
  • 7 Novel Treatment Strategy for GBM
  • Acknowledgments
  • References
  • 16 Esophageal Cancer
  • 1 Introduction
  • 2 DNA Methylation
  • 2.1 Hypermethylated Genes in BE and EAC
  • 2.2 Hypermethylated Genes in ESCC
  • 2.3 TSG Hypermethylation as Biomarker in Esophageal Cancer
  • 2.3.1 TSG hypermethylation as biomarker in EAC
  • 2.3.2 TSG hypermethylation as biomarker in ESCC
  • 3 Dysregulation of miRNA
  • 3.1 miRNAs Profiling and Their Target Genes in Esophageal Cancer
  • 3.1.1 onco-miR
  • 3.1.2 ts-miR
  • 3.2 miRNA as Biomarker in Esophageal Cancer
  • 4 Opportunities to Epigenetically Target Esophageal Cancer
  • 5 Other Epigenetic Events in Esophageal Cancer
  • 5.1 Histone Acetylases/Deacetylases and Histone Methyltransferases/Demethylases
  • 5.2 Long Noncoding RNA
  • References
  • 17 Nasopharyngeal Cancer
  • 1 Introduction
  • 2 DNA Hypermethylation in NPC
  • 3 Histone Modifications in NPC
  • 4 MicroRNA Alterations in NPC
  • 5 Long Noncoding RNAs in NPC
  • 6 Clinical Trials
  • 7 Future Perspectives
  • References
  • 3 Targeting aberrant epigenetics
  • 18 Nutritional Epigenetic Regulators in the Field of Cancer: New Avenues for Chemopreventive Approaches
  • 1 Introduction
  • 2 Overview of the Cancer Epigenome
  • 2.1 Histone Modifications
  • 2.2 DNA Methylation
  • 2.3 Epigenetic Readers
  • 2.4 MicroRNAs
  • 3 Dietary Factors and Their Influence on Epigenetics: Avenue for Dietary Intervention to Prevent Cancer
  • 3.1 Modulation of Epigenetic Cofactors by Nutrients and Metabolism
  • 3.1.1 S-adenosyl methionine
  • 3.1.1.1 Folate
  • 3.1.1.2 Choline and betaine
  • 3.1.1.3 Methionine
  • 3.1.1.4 Vitamins B2, B6, and B12
  • 3.1.2 NAD+
  • 3.1.3 Acetyl-CoA
  • 3.1.4 FAD
  • 3.1.5 a-ketogutarate
  • 3.2 Other Diet-Derived Nutrients Affecting Epigenetic Mechanisms
  • 3.2.1 Selenium
  • 3.2.2 Zinc
  • 3.2.3 Butyrate
  • 3.2.4 Ursodeoxycholic acid
  • 3.3 Phytochemicals Targeting Epigenetic Enzymes
  • 3.3.1 Thiosulfonates
  • 3.3.2 Glucosinates
  • 3.3.2.1 Isothiocyanates
  • 3.3.2.2 Indole-3-carbinol
  • 3.3.3 Polyphenols
  • 3.3.3.1 Anacardic acid
  • 3.3.3.2 Chalcones
  • 3.3.3.3 Curcumin
  • 3.3.3.4 EGCG
  • 3.3.3.5 Genistein and daidzein
  • 3.3.3.6 Quercetin
  • 3.3.3.7 Resveratrol
  • 3.3.4 Other phytochemicals
  • 3.3.4.1 Garcinol
  • 3.3.4.2 Lycopene
  • 4 Conclusions and Critical Considerations
  • Acknowledgments
  • References
  • 19 Emerging Epigenetic Therapies-Lysine Methyltransferase/PRC Complex Inhibitors
  • 1 Introduction
  • 2 PRC2 Structure-Function and Drugability
  • 3 Role of PRC2 in Cancer and EZH2 as a Drug Target
  • 4 Discovery of Inhibitors of EZH2/PRC2
  • 5 Conclusions
  • References
  • 20 Inhibitors of Jumonji C-Domain Histone Demethylases
  • 1 Introduction: Histone Methylation-Normal and Pathological Functions
  • 2 The First Histone Demethylases: LSD1 and LSD2
  • 3 The Jumonji C-Domain Histone Demethylases
  • 4 Role of JMJC Histone Demethylases in Human Cancer
  • 5 Small Compound Inhibitors of JMJC Histone Demethylases
  • 6 Conclusion
  • References
  • 21 Emerging Epigenetic Therapies: Lysine Acetyltransferase Inhibitors
  • 1 Introduction
  • 2 Aberrant Histone Acetylation Patterns in Diseases
  • 3 Role of KATs in Cancer
  • 3.1 p300/CBP Family
  • 3.2 GNAT Family
  • 3.3 MYST Family
  • 3.3.1 Tip60
  • 3.3.2 HBO1
  • 3.3.3 MOZ and MORF
  • 3.3.4 MOF
  • 4 Lysine Acetyltransferases as Potential Therapeutic Targets
  • 4.1 Bisubstrate Inhibitors
  • 4.2 KAT Inhibitors: Natural Products
  • 4.3 KAT Inhibitors: Synthetic Derivatives and Analogs of Natural Products
  • 4.4 KAT Inhibitors: Synthetic Small Molecules
  • 5 Conclusion and Perspective
  • References
  • 22 Emerging Epigenetic Therapies-Bromodomain Ligands
  • 1 Introduction
  • 1.1 Bromodomains-a KAc Recognition Domain
  • 1.2 Classification of Human Bromodomains
  • 1.3 Functions of BET bromodomains
  • 1.4 The roles of BET BCPs in cancer
  • 2 The Development of BET Bromodomain Ligands
  • 2.1 Diazepine-Based BET Bromodomain Ligands
  • 2.1.1 I-BET762 (1)
  • 2.1.2 Mitsubishi compounds and (+)-JQ1 (2)
  • 2.2 3,5-Dimethylisoxazole-Based Bromodomain Ligands
  • 2.3 RVX-208 (5)
  • 2.4 PFI-1 (10)
  • 2.5 Thiazol-2-One-Based Bromodomain Ligands
  • 2.6 Diazobenzene-Based Bromodomain Ligands
  • 2.7 4-Acylpyrroles-XD14 (14)
  • 2.8 I-BET726 (GSK1324726A, 12)
  • 2.9 In Silico Approaches to the Discovery of BET Bromodomain-Binding Fragments
  • 2.10 Dual kinase-bromodomain inhibitors
  • 3 BET Bromodomain Ligands in Clinical Trials
  • 3.1 BET Bromodomain Ligands and Cancer
  • 3.2 BET Bromodomain Ligands and Inflammation
  • 3.3 BET Bromodomain Ligands in Clinical Trials
  • 4 The Development of CREBBP Bromodomain Ligands
  • 4.1 N-Acetylated fragments
  • 4.2 Azobenzene-Based CREBBP Bromodomain Ligands
  • 4.3 A CREBBP Bromodomain-Binding Cyclic Peptide
  • 4.4 Dihydroquinoxalinone-Based CREBBP Bromodomain Ligands
  • 4.5 3,5-Dimethylisoxazole-Based CREBBP Bromodomain Ligands
  • 5 The Development of Ligands for Other Bromodomains
  • 6 Conclusion
  • References
  • 23 Clinical Trials
  • 1 Introduction
  • 2 Single Agent Therapy
  • 2.1 DNA Methyltransferase Inhibitors
  • 2.1.1 Azacitidine
  • 2.1.2 Decitabine
  • 2.1.3 EGCG in clinical trials
  • 2.2 Histone Deacetylase Inhibitors
  • 2.2.1 Hydroxamic acids
  • 2.2.2 Short-chain fatty acids
  • 2.2.3 Benzamides
  • 2.2.4 Cyclic peptides
  • 2.3 Histone Acetylation Transferase (HAT) Inhibitors
  • 3 Combination Therapy
  • 3.1 In Combination with Other Oncology Drugs
  • 3.1.1 Combination of DNMTis with other oncology drugs
  • 3.1.2 Combination of HDACis with other oncology drugs
  • 3.2 In Combination with Other Epigenetic Agents
  • 3.2.1 In hematologic malignancies
  • 3.2.2 In solid tumors
  • 4 Conclusion and Future Perspectives
  • References
  • 4 Issues to overcome/Areas of concern
  • 24 Genetic Intratumor Heterogeneity
  • 1 Introduction: Inter- and Intratumor Heterogeneity
  • 2 Genetic ITH as a Result of Population Expansion
  • 3 Cancer from an Evolutionary Perspective
  • 4 Patterns of ITH
  • 4.1 ITH in Solid Tumors
  • 4.2 ITH in Leukemias
  • 5 ITH and the Evolution of Drug Resistance
  • 6 Clinical Implications of ITH
  • Acknowledgments
  • References
  • 25 Epigenetics Underpinning DNA Damage Repair
  • 1 Introduction
  • 2 Epigenetic Changes in Chromatin
  • 2.1 Histone Modifications
  • 2.2 DNA Methylation
  • 2.3 MicroRNAs
  • 3 DNA Damage
  • 4 DNA Repair Pathways
  • 4.1 Mismatch Repair
  • 4.2 Base Excision Repair
  • 4.3 Nucleotide Excision Repair
  • 4.4 Double-Strand Break Repair
  • 5 Epigenetic Modifications of Double-Strand Break Repair
  • 5.1 DNA Repair-Induced Histone Modifications
  • 5.2 Phosphorylation
  • 5.3 Ubiquitination
  • 5.4 Methylation
  • 5.5 Acetylation and Deacetylation
  • 6 Chromatin Remodeling Factors Recruited to Sites of DNA Damage
  • 7 DNA Repair in Heterochromatin
  • 8 Conclusion
  • References
  • 26 Epigenetics of Cisplatin Resistance
  • 1 Introduction
  • 2 DNA Methylation
  • 2.1 DNA Methylation Changes Associated with Cisplatin Resistance
  • 2.2 Methylation in Cancer Cell Lines May Not Truly Reflect the Methylation from the Primary Tumor
  • 3 Epigenetic Readers, Writers, and Erasers
  • 3.1 Lysine Acetyltransferases
  • 3.2 Tip60/Kat5-A Master Regulator of Cisplatin Resistance
  • 3.3 EZH2/PRC2 Complexes and Cisplatin Resistance
  • 3.4 Epigenetic Erasers Associated with Cisplatin Resistance
  • 3.5 Epigenetic Readers Associated with Cisplatin Resistance
  • 3.6 BRCA1 Complexes Containing Epigenetic Readers/Writers and Erasers as a Critical Element in Cisplatin Resistance
  • 3.6.1 BRCA1 complexes, the epigenetic machinery, and DNA damage responses
  • 3.6.2 BRCA1 is linked with sensitivity to cisplatin
  • 3.6.3 The link between BRCA1, K-methyltransferases, and acquired cisplatin resistance
  • 4 Noncoding RNAs
  • 4.1 miRNAs Associated with Cisplatin Resistance/Sensitivity
  • 4.2 epi-miRNAs and Cisplatin Sensitivity
  • 4.3 lncRNAs Associated with Resistance/Sensitivity
  • 5 Histone Variants
  • 6 Cancer Stem Cells and Cisplatin Resistance
  • 7 Protein PTMs Associated with Development of Cisplatin Resistance
  • 8 Targeting Cisplatin Resistance Epigenetically
  • 8.1 Natural Bioactives
  • 9 Clinical Trials
  • 9.1 Low Dose Therapies as "Epigenetic Priming" Events
  • 10 Conclusion
  • References
  • 27 Therapeutically Targeting Epigenetic Regulation of Cancer Stem Cells
  • 1 Principles of Stem Cell Biology
  • 1.1 Introduction
  • 1.2 Potency
  • 1.3 Maintenance of the SR State
  • 1.4 Asymmetric Division and Differentiation
  • 1.5 Establishment, Growth, and Repair of Tissues
  • 1.6 SC Populations Are Organized as Stem-Progenitor Cell Hierarchies
  • 1.7 SC Properties and Regulation of Cell Cycle Exit
  • 2 Cancer and Cancer Stem Cells
  • 2.1 Introduction
  • 2.2 Development of CSC Theory
  • 2.3 Defining Principles of CSC Theory
  • 2.4 CSCs and Tumor Development
  • 3 Epigenetic Regulation of CSC SR and Differentiation
  • 3.1 Introduction
  • 3.2 Regulation of Pluripotency by Oct4, Sox2, and Nanog
  • 3.3 Epigenetic Regulation of SCs and CSCs by Stemness Signaling Pathways
  • 3.4 Stemness Signaling Pathways and Epigenetic Regulation by miRNAs and DNA Remodeling
  • 3.5 Wnt/ß-Catenin Signaling
  • 3.6 Hedgehog Signaling
  • 3.7 Notch Signaling
  • 3.8 TGF-ß Signaling
  • 4 Therapeutic Targeting of CSCs
  • 4.1 Introduction
  • 4.2 Challenges for CSC Therapeutics
  • 4.3 Targeting CSCs via Forced Differentiation
  • 4.4 Targeting CSCs via Wnt Signaling
  • 4.5 Targeting CSCs via Hedgehog Signaling
  • 4.6 Targeting CSCs via Notch Signaling
  • 4.7 Targeting CSCs via TGF-ß Signaling
  • 4.8 Targeting CSCs via PRC2 Component EZH2
  • 4.9 Targeting CSCs via miRNA Mechanisms
  • 5 Perspective: CSCs and the Future of Cancer Therapeutics
  • 5.1 Epigenetic CSC Signatures as Biomarkers
  • 5.2 Fighting Fire with Fire: Awakening CSCs for Enhanced Chemoresponse
  • 5.3 Zero-Collateral CSC Targeting
  • References
  • 5 Future Directions: Translation to the Clinic
  • 28 Personalized Epigenetic Therapy-Chemosensitivity Testing
  • 1 Introduction
  • 2 Chemoresistance in Lymphomas
  • 3 Epigenetically Encoded Chemoresistance
  • 4 Implementing Epigenetic Therapy to Chemosensitize Lymphoma
  • 5 What Antitumoral Effect to Expect from Epigenetic Drugs?
  • 6 Selecting the Right Drug for the Right Patient and Vice Versa
  • 6.1 Cellular Reprogramming
  • 6.2 Synthetic Lethality
  • 7 Resistance to Epigenetic-Acting Drugs and Chemosensitivity Testing
  • 8 Conclusion
  • References
  • 29 Personalized Therapy-Epigenetic Profiling as Predictors of Prognosis and Response
  • 1 Epigenetic Biomarkers for Precision Medicine
  • 2 Systems Epigenomics for Biomarker Discovery
  • 2.1 Functional Epigenetic Alterations
  • 2.2 Epigenetic Surrogate Biomarker
  • 3 Epigenetic Biomarkers for Diagnosis, Prognosis, and Drug Response
  • 3.1 Diagnostic Epigenetic Biomarkers
  • 3.1.1 Biomarkers in biological fluids
  • 3.1.2 Cancer of unknown primary
  • 3.2 Prognostic Epigenetic Biomarkers
  • 3.3 Biomarker Guiding Therapeutic Decision
  • 3.3.1 Direct implications of epigenetic silencing on drug response
  • 3.3.2 Synthetic lethal interactions of epigenetic events
  • 3.3.3 Lessons learned from genetic biomarker screenings
  • 4 Genetic Alterations in Epigenetic Modifiers: Potential Drug Targets
  • 4.1 Epigenetic Drugs in Clinical Use and Trials
  • 4.2 Application of Epigenetic Therapeutics in a Noncancer Context
  • 4.3 A New Generation of Targeted Epigenetic Drugs
  • 5 Future Perspective of Biomarker Discovery and Application
  • References
  • Index

List of Contributors


Bryce K. Allen,     Center for Therapeutic Innovation, The Miami Project to Cure Paralysis, Department of Psychiatry and Behavioral Sciences, University of Miami Miller School of Medicine, Miami, FL, USA

Donat Alpar,     Centre for Evolution and Cancer, The Institute of Cancer Research, London, UK

Viren Amin,     Epigenome Center, Baylor College of Medicine, Houston, Texas, USA

Fazila Asmar,     Department of Hematology, Rigshospitalet, Copenhagen, Denmark

Nagi G. Ayad,     Center for Therapeutic Innovation, The Miami Project to Cure Paralysis, Department of Psychiatry and Behavioral Sciences, University of Miami Miller School of Medicine, Miami, FL, USA

Anne-Marie Baird

Genome Stability Laboratory, Cancer and Ageing Research Program, Institute of Health and Biomedical Innovation, Queensland University of Technology, Woolloongabba, Queensland, Australia

Thoracic Oncology Research Group, Institute of Molecular Medicine, St. James's Hospital, Dublin, Ireland

Louise J. Barber,     Centre for Evolution and Cancer, The Institute of Cancer Research, London, UK

Becky A.S. Bibby,     Cancer Biology and Therapeutics Lab, School of Biological, Biomedical and Environmental Sciences, University of Hull, Yorkshire, UK

Emma Bolderson,     Genome Stability Laboratory, Cancer and Ageing Research Program, Institute of Health and Biomedical Innovation, Queensland University of Technology, Woolloongabba, Queensland, Australia

Philippe Bouvet,     Laboratoire Joliot-Curie, Ecole Normale Supérieure de Lyon, Université de Lyon, Lyon, France

Frédéric Catez

Centre de Recherche en Cancérologie de Lyon, Centre Léon Bérard, Lyon, France

Université de Lyon, Lyon, France

Leandro Cerchietti,     Hematology and Oncology Division, Medicine Department, Weill Cornell Medical College of Cornell University, New York, NY, USA

Snehajyoti Chatterjee

Transcription and Disease Laboratory, Molecular Biology and Genetics Unit, Jawaharlal Nehru Centre for Advanced Scientific Research, Bangalore, Karnataka, India

Laboratoire de Neurosciences Cognitives et Adaptatives, Université de Strasbourg-CNRS, GDR CNRS, Strasbourg, France

Taiping Chen

Department of Molecular Carcinogenesis and the Center for Cancer Epigenetics, The University of Texas MD Anderson Cancer Center, Smithville, Texas, USA

The University of Texas Graduate School of Biomedical Sciences at Houston, Houston, Texas, USA

Andreas I. Constantinou,     Laboratory of Cancer Biology and Chemoprevention, Department of Biological Sciences, School of Pure and Applied Sciences, University of Cyprus, Nicosia, Cyprus

Stuart J. Conway,     Department of Chemistry, Chemistry Research Laboratory, University of Oxford, Oxford, UK

Dashyant Dhanak,     Janssen Research & Development, Spring House, PA, USA

Jean-Jacques Diaz

Centre de Recherche en Cancérologie de Lyon, Centre Léon Bérard, Lyon, France

Université de Lyon, Lyon, France

Marc Diederich,     College of Pharmacy, Seoul National University, Gwanak-gu, Seoul, Korea

Xinmin Fan,     Department of Pathology, The Shenzhen University School of Medicine, Shenzhen, Guangdong, People's Republic of China

Brendan Ffrench,     Department of Pathology, Coombe Women's and Infant's University Hospital, Dublin, Ireland

Michael F. Gallagher,     Department of Histopathology, University of Dublin, Trinity College, Trinity Centre, St James Hospital, Dublin, Ireland

Marco Gerlinger,     Centre for Evolution and Cancer, The Institute of Cancer Research, London, UK

Steven D. Gore,     Department of Internal Medicine (Hematology), Yale Cancer Center, New Haven, CT, USA

Steven G. Gray

HOPE Directorate, St. James's Hospital, Dublin, Ireland

Thoracic Oncology Research Group, Institute of Molecular Medicine, St. James's Hospital, Dublin, Ireland

Kirsten Grønbæk,     Department of Hematology, Rigshospitalet, Copenhagen, Denmark

David S. Hewings,     Department of Chemistry, Chemistry Research Laboratory, University of Oxford, Oxford, UK

Holger Heyn,     Cancer Epigenetics and Biology Program, Bellvitge Biomedical Research Institute, Barcelona, Catalonia, Spain

Zhe Jin

Department of Pathology, The Shenzhen University School of Medicine, Shenzhen, Guangdong, People's Republic of China

Shenzhen Key Laboratory of Micromolecule Innovatal Drugs, The Shenzhen University School of Medicine, Shenzhen, Guangdong, People's Republic of China

Shenzhen Key Laboratory of Translational Medicine of Tumor, The Shenzhen University School of Medicine, Shenzhen, Guangdong, People's Republic of China

Stephanie Kaypee,     Transcription and Disease Laboratory, Molecular Biology and Genetics Unit, Jawaharlal Nehru Centre for Advanced Scientific Research, Bangalore, Karnataka, India

Yutaka Kondo,     Department of Epigenomics, Nagoya City University Graduate School of Medical Sciences, Mizuho-cho, Mizuho-ku, Nagoya, Japan

Tapas K. Kundu,     Transcription and Disease Laboratory, Molecular Biology and Genetics Unit, Jawaharlal Nehru Centre for Advanced Scientific Research, Bangalore, Karnataka, India

Florian Laforêts

Centre de Recherche en Cancérologie de Lyon, Centre Léon Bérard, Lyon, France

Université de Lyon, Lyon, France

Matthew W. Lawless,     Experimental Medicine, UCD School of Medicine and Medical Science, Mater Misericordiae University Hospital, Catherine McAuley Centre, Dublin, Ireland

Stephen G. Maher,     Cancer Biology and Therapeutics Lab, School of Biological, Biomedical and Environmental Sciences, University of Hull, Yorkshire, UK

Somnath Mandal

Transcription and Disease Laboratory, Molecular Biology and Genetics Unit, Jawaharlal Nehru Centre for Advanced Scientific Research, Bangalore, Karnataka, India

Department of Biochemistry, Faculty of Agriculture, Uttar Banga Krishi Viswavidyalaya, Pundibari, Cooch-Behar, West Bengal, India

Virginie Marcel

Centre de Recherche en Cancérologie de Lyon, Centre Léon Bérard, Lyon, France

Université de Lyon, Lyon, France

Aleksandar Milosavljevic,     Epigenome Center, Baylor College of Medicine, Houston, Texas, USA

Hannah L. Moody

Cancer Biology and Therapeutics Lab, School of Biological, Biomedical and Environmental Sciences, University of Hull, Yorkshire, UK

Hull York Medical School, Yorkshire, UK

Atsushi Natsume,     Department of Neurosurgery, Nagoya University Graduate School of Medicine, Nagoya, Japan

Thomas B. Nicholson,     Developmental and Molecular Pathways, Novartis Institutes for BioMedical Research, Cambridge, MA, USA

Kenneth J. O'Byrne

Genome Stability Laboratory, Cancer and Ageing Research Program, Institute of Health and Biomedical Innovation, Queensland University of Technology, Woolloongabba, Queensland, Australia

Thoracic Oncology Research Group, Institute of Molecular Medicine, St. James's Hospital, Dublin, Ireland

Shane O'Grady,     Experimental Medicine, UCD School of Medicine and Medical Science, Mater Misericordiae University Hospital, Catherine McAuley Centre, Dublin, Ireland

John J. O'Leary,     Department of Pathology, Coombe Women's and Infant's University Hospital, Dublin, Ireland

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