Advances in cancer genomics are transforming our understanding of cancer, and have profound implications for its prevention, diagnosis, and treatment. Evolutionary dynamics suggests that as few as two mutations can cause transformation of normal cells into cancer stem cells. A process of Darwinian selection, involving a further three or more mutations, taking place over a period of years, can then result in progression to a life-threatening tumour. In many cases the immune response can recognise and eliminate the mutant cells, but most advanced tumours have mutations that activate immune checkpoints and enable the tumour to hide from the immune system. For the most hard-to-treat tumours, future progress will require molecular diagnostics to detect cancer-causing mutations in healthy subjects, and new drugs or vaccines that prevent the progression process.
Chapters of this book deal with the signalling pathways that control cell division, and changes in these pathways in cancer cells. Three cell cycle checkpoints that are often mutated in cancer are analysed in detail. A discussion of chronic myeloid leukaemia illustrates the role of reactive oxygen species in driving progression from a chronic to an acute condition. A single drug that suppresses reactive oxygen can prevent disease progression and turn an otherwise deadly disease into a condition that can be managed to enable many years of normal life. Another chapter discusses chronic myelomonocytic leukaemia, a disease that involves both genetic and epigenetic change. Tumour progression is discussed as a multi-stage process in which cancer stem cells evolve into genetically unstable, invasive, metastatic, drug-resistant growths. Each of these stages can act as targets for drugs or immunomodulators, but the future of cancer treatment lies in understanding tumour dynamics, and arresting malignancy at the earliest possible stage.
Evolutionary dynamics is a primarily mathematical technique, but the target readership will be tumour biologists, clinicians, and drug developers. Computational detail is provided in an online supplement, but the main text emphasises the implications of the dynamics for an understanding of tumour biology and does not require mathematical expertise.
Author(s): Robert C. Jackson
Publisher: Springer
Year: 2023
Language: English
Pages: 270
City: Cham
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
