Evolutionary Dynamics of Malignancy: The Genetic and Environmental Causes of Cancer

Acknowledgments
Contents
Abbreviations
Chapter 1: Cancer as a Disease of Cell Proliferation
	1.1 What Is Evolutionary Dynamics?
	1.2 Cancer Enzymology
	1.3 Oncogenes and Tumour Suppressor Genes
	1.4 Signalling Pathways
	1.5 Signalling Dynamics: ON/OFF Switches and Volume Controls
	1.6 Dynamics of Tumour Growth
	1.7 The Hallmarks of Cancer
	1.8 Methotrexate: An Antiproliferative Drug
	References
Chapter 2: Genetic and Chromosomal Instability
	2.1 Cancer as a Disease of Ageing
	2.2 Radiation and Chemical Carcinogenesis
	2.3 Viral Carcinogenesis
	2.4 Burkitt´s Lymphoma and Chromosomal Translocation
	2.5 Aneuploidy and Duesberg´s Hypothesis
	2.6 Differences Between Carcinomas and Lymphomas
	2.7 Microsatellite Instability
	2.8 Tumour Heterogeneity
	2.9 Cancer Genome Projects: Driver and Passenger Mutations
	2.10 Replicative Stress and Chromosomal Instability
	2.11 Modelling Mutations with a Genetic Algorithm
	2.12 Polyploidy
	2.13 Mutation Rates and Lifetime Cancer Risk
	2.14 Alkylating Agents: Drugs that Cross-Link DNA
	References
Chapter 3: Cancer as a Disease of Defective Cell Cycle Checkpoint Function
	3.1 Differentiation or Cell Division?
	3.2 The Mammalian Cell Cycle
	3.3 P53, the Guardian of the Genome
	3.4 The G1:S Checkpoint
	3.5 Mutations that Inactivate or Over-Ride the Checkpoint
	3.6 Benign Hyperplasia and Premalignant Conditions
	3.7 Inhibitors of Cyclin-Dependent Kinases
	3.8 The CYCLOPS Model of the Cell Cycle
	3.9 Palbociclib-Induced Cell Cycle Arrest
	3.10 Selectivity of Signalling Pathway Inhibition Against Mutants
	References
Chapter 4: The DNA Damage Checkpoint
	4.1 DNA Repair Pathways
	4.2 Selectivity of DNA-Damaging Drugs
	4.3 Mutant or Abnormally Expressed DNA Repair Enzymes in Tumours
	4.4 Cross-Talk Between the DNA Damage Checkpoint and the SAC
	4.5 Replication Catastrophe
	4.6 Modelling Inhibition of the DDR
	4.7 Kinetics of the Checkpoint
	4.8 Olaparib: An Inhibitor of the DDR
	References
Chapter 5: Dynamics of the Spindle Assembly Checkpoint
	5.1 The Mitotic Spindle
	5.2 Mitotic index as a Measure of Cell Proliferation
	5.3 The Spindle Assembly Checkpoint
	5.4 The SAC as Guardian of the Karyotype
	5.5 SAC Over-Ride and Cancer
	5.6 Loss-of-Function Mutations in the SAC
	5.7 Inhibitors of SAC Components as Anticancer Drugs
	5.8 The SAC and Speciation
	5.9 Modelling Checkpoint Mutations with a Finite State Machine
	5.10 A Kinetic Model of the SAC
	5.11 The Two Checkpoints Theory of Cancer
	References
Chapter 6: Dynamics of Drug Resistance
	6.1 Luria and Delbruck´s Fluctuation Equation
	6.2 The Model of Goldie and Coldman
	6.3 Intrinsic and Acquired Drug Resistance
	6.4 In Vitro, In Vivo and Clinical Endpoints for Chemotherapy
	6.5 Mechanisms of Acquired Drug Resistance
	6.6 Evolutionary Dynamics of Drug Resistance
	6.7 Model Validation and Interspecies Scaling
	6.8 Principles of Combination Chemotherapy
	6.9 Adaptive Cancer Therapy
	6.10 Cisplatin: A Magic Bullet?
	References
Chapter 7: Chronic Myeloid Leukaemia: A One-Hit Malignancy
	7.1 CML as a Disease of Redox Imbalance
	7.2 The Philadelphia Chromosome and the Bcr-Abl Translocation
	7.3 CML as a Constitutively Activated Innate Immune Response
	7.4 Mcl-1 and Myeloid Cell Immortalisation
	7.5 Reactive Oxygen Species, Ageing, and Cancer
	7.6 8-Oxoguanine as a Mutagen
	7.7 Imatinib in the Treatment of CML
	7.8 Modelling the Evolutionary Dynamics of CML
	References
Chapter 8: Chronic Myelomonocytic Leukaemia: A Three-Hit Malignancy
	8.1 Cancer as a Disease of Ageing: The Age Distribution of CMML
	8.2 Epigenetic Changes in Malignancy
	8.3 Epigenetic Gene Silencing and the Role of TET2
	8.4 Loss-of-Function Mutations and Tumour Suppressor Genes
	8.5 Hypomethylating Agents as Treatments for CMML
	8.6 Evolutionary Dynamics of CMML
	References
Chapter 9: The Cancer Stem Cell and Tumour Progression
	9.1 Tumour Progression as a Process of Natural Selection
	9.2 Origins of Cancer Stem Cells
	9.3 Driver and Passenger Mutations in Tumour Progression
	9.4 De-differentiation
	9.5 Angiogenesis as an Aspect of Tumour Progression
	9.6 The Warburg Effect
	9.7 The Epithelial-Mesenchymal Transition
	9.8 Metastasis as an Aspect of Tumour Progression
	9.9 Modelling Metastasis
	9.10 The Big Bang Model of Tumour Growth
	9.11 Antiandrogens in Treatment of Prostate Cancer
	References
Chapter 10: Evading the Antitumour Immune Response
	10.1 Cells of the Immune System
	10.2 The Major Histocompatibility Complex
	10.3 Immunotherapy
	10.4 Escape from Immune Surveillance
	10.5 Immune Checkpoint Inhibitors
	10.6 Cancer Vaccines in Treatment and Prevention
	10.7 Cellular Immunotherapy
	10.8 Modelling Antitumour Immunity
	References
Chapter 11: Implications of Evolutionary Dynamics for Cancer Treatment and Prevention
	11.1 Current Views of the Causes of Cancer
	11.2 Implications of Evolutionary Dynamics for Diagnosis
	11.3 Implications of Evolutionary Dynamics for Cancer Treatment
	11.4 Implications of Evolutionary Dynamics for Tumour Prevention
	11.5 Manipulating the Environment to Reduce Cancer Incidence
	11.6 Using Drugs to Inhibit Tumour Progression
	11.7 Artificial Intelligence Systems for Predicting Tumour Progression
	11.8 In Silico Clinical Trial Modelling
	11.9 Clinical Endpoints: Progression-Free Survival
	11.10 Cytotoxicity and Cytostasis
	11.11 The Potential Role of Cancer Vaccines
	References
Chapter 12: In Science All Conclusions Are Provisional
	12.1 Why Has Cancer Been an Exception in the March of Medical Progress?
	12.2 Deterministic and Probabilistic Events in Models of Malignancy
	12.3 One-Hit, Two-Hit, and Three-Hit Malignancies: Causes and Consequences
	12.4 Major Ideas in the Development of the Evolutionary Dynamics of Malignancy
	12.5 All Stages of Transformation and Progression Have Been Targeted by Anticancer Drugs
	12.6 Future Progress Will Require a Deeper Understanding of Malignant Progression
	12.7 Unanswered Questions that May Be Studied by Evolutionary Dynamics
	12.8 Cancer as a Disease of Gene Expression
	References
Appendix: Using the Online Supplements
Index