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DNA Repair in Cancer Therapy
Molecular Targets and Clinical Applications
2nd Edition - June 7, 2016
Editors: Mark R. Kelley, Melissa L. Fishel
Hardback ISBN:9780128035825
9 7 8 - 0 - 1 2 - 8 0 3 5 8 2 - 5
eBook ISBN:9780128035993
9 7 8 - 0 - 1 2 - 8 0 3 5 9 9 - 3
DNA Repair and Cancer Therapy: Molecular Targets and Clinical Applications, Second Edition provides a comprehensive and timely reference that focuses on the translational and… Read more
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DNA Repair and Cancer Therapy: Molecular Targets and Clinical Applications, Second Edition provides a comprehensive and timely reference that focuses on the translational and clinical use of DNA repair as a target area for the development of diagnostic biomarkers and the enhancement of cancer treatment.
Experts on DNA repair proteins from all areas of cancer biology research take readers from bench research to new therapeutic approaches. This book provides a detailed discussion of combination therapies, in other words, how the inhibition of repair pathways can be coupled with chemotherapy, radiation, or DNA damaging drugs.
Newer areas in this edition include the role of DNA repair in chemotherapy induced peripheral neuropathy, radiation DNA damage, Fanconi anemia cross-link repair, translesion DNA polymerases, BRCA1-BRCA2 pathway for HR and synthetic lethality, and mechanisms of resistance to clinical PARP inhibitors.
Provides a comprehensive overview of the basic and translational research in DNA repair as a cancer therapeutic target
Includes timely updates from the earlier edition, including Fanconi Anemia cross-link repair, translesion DNA polymerases, chemotherapy induced peripheral neuropathy, and many other new areas within DNA repair and cancer therapy
Saves academic, medical, and pharma researchers time by allowing them to quickly access the very latest details on DNA repair and cancer therapy
Assists researchers and research clinicians in understanding the importance of the breakthroughs that are contributing to advances in disease-specific research
Basic science and translational cancer researchers, geneticists, clinical geneticists, oncologists, radiation oncologists, cell biologists, pharmaceutical scientists, toxicologists, others interested in DNA repair in cancer therapy
List of Contributors
Preface
Acknowledgments
Chapter 1: Overview of DNA repair pathways, current targets, and clinical trials bench to clinic
Abstract
Introduction
Overview of DNA Repair Pathways
MGMT Inhibition: First Foray Into DNA Repair Inhibition
PARP: The Archetypical Inhibitor
Synthetic Lethality: Targeting a Cell That is Already Genetically Unstable
DNA Damage Checkpoints
Inhibitors in Development
Future Perspectives
Acknowledgments
Chapter 2: MGMT—a critical DNA repair gene target for chemotherapy resistance
Abstract
Cell Death Pathways Triggered by O6-Alkylating Anticancer Drugs
Repair of O6-Alkylated DNA by MGMT
Regulation of MGMT
Expression of MGMT in Normal and Malignant Cells
MGMT as Prognostic/Predicting Factor in Cancer Therapy
MGMT Polymorphisms in Cancer Therapy
Targeting MGMT in Cancer Therapy
Conclusions
Chapter 3: Understanding the basics for translating the base excision repair pathway from benchtop to bedside in cancer treatment
Abstract
Base Excision Repair: A Pathway for Small Lesions Having Big Consequences for Cancer Cells
Central Role of APE1 in BER and Its Relevance to Cancer Biology
The APE1/NPM1 Interaction in Cancer
BER as a Promising Target to Improve Cancer Therapy
Acknowledgments
Chapter 4: The role of PARP in DNA repair and its therapeutic exploitation
Abstract
Introduction
Poly(ADP-ribose) Polymerases
Preclinical Data Supporting Clinical Development of PARP Inhibitors
Potentiation of the Cytotoxicity on DNA Damaging Chemotherapy Agents
Single Agent Activity of PARP Inhibitors
Potentiation of the Cytotoxicity of Radiotherapy
PARP Trapping—A Novel Mechanism of PARP Inhibitors
Clinical Development of PARP Inhibitors
First Clinical Trial
Chemotherapy Combination Studies
Synthetic Lethality in HR Deficiency
Single-Agent Data Leading to License of Olaparib
Biomarker Refinement to Identify Patients With HRD Tumors
Chapter 5: Targeting the nucleotide excision repair pathway for therapeutic applications
Abstract
The Nucleotide Excision Repair Pathway
Targeting NER in Combination with DNA Damaging Chemotherapy
Targeting ERCC1/XPF
Targeting DNA Damage Recognition and Verification via XPA
Targeting the Multifunctional RPA DNA-Binding Protein
Alternative Mechanisms of NER Inhibition
Conclusions and Perspective for the Future
Chapter 6: The DNA mismatch repair pathway
Abstract
The Canonical MMR Pathway
Mitochondrial Mismatch Repair
Treating DNA Repair Deficient Cancers
New Ways to Treat DNA Mismatch Repair Deficient Cancers
Conclusions
Chapter 7: Chemotherapeutic intervention by inhibiting DNA polymerases
Abstract
The Impact of Chemotherapeutic Agents on DNA Synthesis
DNA Polymerases
Classification of DNA Polymerases
Structural Features of DNA Polymerases
Kinetic and Chemical Mechanisms of DNA Polymerization
Exonuclease Proofreading
Effects of DNA-Damaging Agents on DNA Polymerization
The Role of DNA Polymerases in DNA Repair
General Strategies to Inhibit DNA Polymerase Activity
Clinical Utility of Purine Nucleoside Analogs
Pharmacokinetic Features of Purine Nucleoside Analogs
Biochemical Mechanism of Action
Other Cytotoxic Mechanisms of Fludarabine
Clinical Activity of Fludarabine as a Monotherapeutic Agent
Clinical and Biochemical Studies of Fludarabine Combined with DNA-Damaging Agents
Other Purine Nucleoside Analogs
Clinical Utility of Pyrimidine Nucleoside Analogs
Pharmacokinetic Properties of Pyrimidine Nucleosides
Mechanism of Action
Clinical Utility of Gemcitabine as a Monotherapeutic Agent
Clinical and Biochemical Studies of Gemcitabine Combined with DNA-Damaging Agents
Potential Mechanisms for Synergistic Activity
Nucleoside Analogs as Radiosensitizers
Clinical Complications Associated with Nucleoside Analogs
Emerging Areas in Chemotherapeutic Intervention
Chapter 8: Targeting homologous recombination repair in cancer
Abstract
Mechanisms and Regulation of Homologous Recombination Repair
Conclusions
Homologous Recombination Repair and Cancer
Strategies for Targeting Homologous Recombination Repair in Cancer
Conclusions
Acknowledgments
List of acronyms and abbreviations
Glossary
Chapter 9: DNA double-strand repair by nonhomologous end joining and its clinical relevance
Abstract
Introduction
Canonical NHEJ
Noncanonical NHEJ
Opportunities for Therapeutic Targeting
Conclusions
Chapter 10: Diversity and implication of MAPK signal transduction involved in the regulation of chemotherapy-induced DNA damage response
Abstract
Introduction
Growth Factor Receptor-Coupled Signal Transduction Pathways That Are Points of Convergence for DNA Damage Response and DNA Repair
Signal Transduction Pathways That Regulate Effectors of the DNA-Damage Response
Kinases Involved in Phosphorylation of DNA Repair Proteins
Histone Modifiers Implicated in the Regulation of DNA Damage Response and DNA Repair
Targeting the MAPK Signal Transduction Pathways for Modulation of Chemotherapy-Induced DNA Damage and Therapeutic Response
Concluding Remarks and Perspectives
Acknowledgments
List of Acronyms and Abbreviations
Chapter 11: Radiation DNA damage and use in cancer/therapeutics-translation of radiation modifiers
Abstract
Introduction
Induction and Repair of DNA Damage
Radiotherapy
Targeting
Prediction
Conclusions
Chapter 12: The FANCA to FANCZ of DNA interstrand crosslink repair: Lessons from Fanconi anemia
Abstract
Introduction
Fanconi Anemia: Disease and Diagnosis
Fanconi Anemia: Genetics and Phylogeny
FA/BRCA ICL Repair Pathway
Sensing ICL
Signaling ICL via the FA Core Complex
What Does Ubiquitination Do To FANCD2 and FANCI?
Deubiquitination of FANCI:FANCD2 During ICL Repair
Unloading CMG Helicase and Strand Cleavage
Homologous Recombination Repair, Translesion Synthesis, and Completion of Replication
Cell Cycle Effects Post ICL Damage, Link to FA
ICLs and Chemotherapy
Side-Effects in Clinical Use of ICL Generating Agents
ICLs as Cancer Causing Agents
Increasing the Efficacy of ICL Inducing Agents
Increasing Efficacy of ICL Damage by Protecting Normal Cells
Conclusions
Chapter 13: The role of DNA damage and repair in toxicity to postmitotic cells caused by cancer therapies
Abstract
Introduction
Cancer Therapy-Induced Neurotoxicity
Cancer Therapy-Induced Cardiotoxicity
Cancer Therapy-Induced Toxicity to Skeletal Muscle
DNA Damage and Repair in Neurons
DNA Damage and Repair in Cardiac Muscle
DNA Damage and Repair in Skeletal Muscle
DNA Damage and Repair Alter Toxicity Induced by Cancer Therapies
Summary
Subject Index
No. of pages: 464
Language: English
Published: June 7, 2016
Imprint: Academic Press
Hardback ISBN: 9780128035825
eBook ISBN: 9780128035993
MK
Mark R. Kelley
Mark R. Kelley, PhD is currently the Betty and Earl Herr Chair in Pediatric Oncology Research, Associate Director for the Herman B Wells Center for Pediatric Research, and the Associate Director of Basic Science Research at the IU Simon Cancer Center. Dr. Kelley’s laboratory studies DNA base excision repair in normal and tumor cells, including the study of DNA repair genes in cognitive dysfunction and peripheral neuropathy. He holds 10 patents related to the use of DNA repair targets for cancer therapy and serves on the consulting and scientific boards of several companies. Thus far Dr. Kelley’s research resulted in over 160 articles published in peer reviewed journals along with numerous reviews and book chapters.
Affiliations and expertise
Professor, Department of Pharmacology and Toxicology, Indiana University School of Medicine, Indianapolis, IN, USA
MF
Melissa L. Fishel
Dr. Fishel is a DNA repair expert who is highly published and is at the forefront in the development of new tumor models focusing on DNA repair pathways in cancer.
Affiliations and expertise
Assistant Research Professor of Pediatric Oncology, Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN, USA