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Animal Models for Human Cancer: Discovery and Development of Novel Therapeutics

Marianne I. Martic-Kehl (Editor), Pius August Schubiger (Editor), Raimund Mannhold (Series Editor), Hugo Kubinyi (Series Editor), Gerd Folkers (Series Editor)
ISBN: 978-3-527-33997-6
272 pages
August 2016
Animal Models for Human Cancer: Discovery and Development of Novel Therapeutics (3527339973) cover image


Based on results from the past ten years, this ready reference systematically describes how to prepare, carry out, and evaluate animal studies for cancer therapies, addressing the widely recognized lack of reliable and reproducible results.
Following a short historical introduction and a discussion of the ethics surrounding animal experiments, the book describes correct study design as well as the handling and housing of animals. It then goes on to describe the animal models available for different cancer types, from natural cancer models in mice and dogs to humanized animals. An evaluation of previously unpublished long-term data from the Swiss canine and feline cancer registry is also included. The final part of the book reviews the lessons learned over the last decade on how to interpret data from animal studies for improving human therapy and gives recommendations for future drug development.
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Table of Contents

List of Contributors XI

Preface XV

A Personal Foreword XVII

1 Introduction 1
Marianne Isabelle Martic-Kehl, Michael F.W. Festing, Carlos Alvarez, and P. August Schubiger

1.1 Animal Models in Biomedical Research 1

1.2 Animals in the Drug Development Process: Historic Background 2

1.3 Problems with Translation of Animal Data to the Clinic 5

1.4 Animal Studies in Anti-cancer Drug Development 6

1.5 Toward Relevant Animal Data 7

1.6 Aim of the Book 8

References 8

2 Ethical Aspects of the Use of Animals in Translational Research 11
Karin Blumer

2.1 Introduction 11

2.2 Today’s R&D Environment 11

2.2.1 Four Emerging Trends Shaping Today’s Debate 13 Growing Lack of Awareness of the Nature of Science and Research 13 Increased Pressure on Basic Research 14 Pressure to Assign “Special” Animals a Special Moral and Legal Status 15 A Reductionist Approach to the 3Rs 16

2.2.2 Preliminary Conclusions 17

2.3 “Do No Harm”: the Essential Dilemma of Animal Research 17

2.4 Man and Animals in Philosophy: an Overview of Key Concepts 18

2.4.1 Anthropocentrism 19

2.4.2 Physiocentric Positions 19 Holistic Concepts 19 Radical Biocentrism 20 Pathocentrism 21 Moderate Biocentrism 22

2.5 Conclusions: Solving the Dilemma 23

References 24

3 Study Design 27
Michael F.W. Festing

3.1 Introduction 27

3.2 Design Principles 28

3.3 Experimental Design 28

3.3.1 The Five Characteristics of aWell-Designed Experiment 29

3.3.2 The Determination of Sample Size 34 Power Analysis for the Determination of Sample Size 34 The Resource Equation Method of Determining Sample Size 36

3.3.3 Formal Experimental Designs 36

3.4 Conclusion 39

References 39

4 Improving External Validity of Experimental Animal Data 41
S. Helene Richter, Chiara Spinello, and Simone Macrì

4.1 Introduction 41

4.1.1 Individual Phenotype Is the Result of Genetic and Environmental Influences 41

4.1.2 Why Do Living Organisms Vary? 42

4.2 Variation in the Laboratory 43

4.2.1 How Is Inter-individual Variability Generally DealtWith? 43 Genetic Standardization 44 Environmental Standardization 44 Standardization of the Test Situation 46

4.3 The Fallacies 46

4.3.1 The Standardization Fallacy 46

4.3.2 The Developmental Match Fallacy 47

4.4 Future Perspectives: an Experimental Strategy Integrating Adaptive Plasticity and Fundamental Methodology 48

4.4.1 AWay Out of the Standardization Fallacy? 48

4.4.2 Favoring Adaptive Plasticity through the Provision of Test Strategies Matching Developmental Cues 53

References 55

5 How to End Selective Reporting in Animal Research 61
Gerben ter Riet and Lex M. Bouter

5.1 Introduction 61

5.2 Definition and Different Manifestations of Reporting Bias 63

5.3 Magnitude of Reporting Biases 63

5.4 Consequences 65

5.4.1 Consequences of Reporting Bias in Human Randomized Trials 65

5.4.2 Consequences of Reporting Bias in Experimental Animal Research 66

5.5 Causes of Reporting Bias 66

5.6 Solutions 68

References 73

6 A Comprehensive Overview of MouseModels in Oncology 79
Divya Vats

6.1 Introduction 79

6.2 Xenograft Mouse Models 81

6.2.1 Cell-Line Xenograft Model 81

6.2.2 Patient-derived Xenografts 82

6.3 Genetically Engineered Mouse Models 83

6.3.1 Limitations 85

6.3.2 Chemical Carcinogenesis: N-ethyl-N-nitrosourea Mutagenesis 86 Alkylnitrosamide Compounds 86

6.3.3 Generation of a Transgenic Mouse Using Pronuclear Injections: Direct Insertion of DNA into Fertilized Zygote 87

6.3.4 Gene Targeting via Homologous Recombination in Embryonic Stem Cells: Gene Knockouts and Knock-Ins 87

6.3.5 Conditional Inactivation (or Activation) of Genes 89

6.3.6 Inducible Systems for Gene Targeting 90

6.3.7 RNA Interference for Gene Knockdown 92

6.4 Applications for GEMMs in Compound Development 93

6.4.1 Target Validation and Compound Testing 93

6.4.2 Chemoresistance and Toxicity 94

6.4.3 In vivo Imaging 94

6.5 Humanized Mouse Models: toward a More Predictive Preclinical Mouse Model 95

6.6 Conclusions: Potentials, Limitations, and Future Directions for Mouse Models in Cancer Drug Development 98

6.6.1 Potentials and Limitations 98

6.6.2 Future Directions 100

References 101

7 Mouse Models of Advanced Spontaneous Metastasis for Experimental Therapeutics 109
Karla Parra, Irving Miramontes, Giulio Francia, and Robert S. Kerbel

7.1 Mouse Tumor Models in Cancer Research 109

7.2 The Evolution of Metronomic Chemotherapy 110

7.3 Development of Highly Aggressive and Spontaneously Metastatic Breast Cancer Models 112

7.4 IsThere Any Evidence that Models of Advanced Metastatic Disease Have the Potential to Improve Predicting Future Outcomes of a GivenTherapy in Patients? 113

7.5 Metronomic Chemotherapy Evaluation in Preclinical Metastasis Models 116

7.6 ExperimentalTherapeutics Using Metastatic Her-2 Positive Breast Cancer Xenografts Models 116

7.7 Examples of Recently Developed Orthotopic Models of Human Cancers 119

7.8 Factors that Can Affect the Usefulness of Preclinical Models in Evaluating NewTherapies 120

7.9 Monitoring Metastatic Disease Progression in Preclinical Models 120

7.10 Alternative Preclinical Models: PDX and GEMMs 121

7.11 Recommendations for the Evaluation of Anti-cancer Drugs Using Preclinical Models 122

7.12 Summary 123

References 124

8 Spontaneous Animal Tumor Models 129
Andreas Pospischil, Katrin Grüntzig, Ramona Graf, and Gianluca Boo

8.1 Introduction 129

8.2 Advantages of Spontaneous Canine/Feline Cancer Registries 130

8.2.1 Effective and Relevant Canine/Feline Cancer Registries – Necessary Steps and Existing Registries 131 Regional/National/International Population-based Human Cancer Registry with Sufficient Case Numbers and Patient Data 131 Regional/National Population-based Canine/Feline Cancer Registries 132 Comparative (Human/Canine/Feline) Geographic and Environmental Risk Assessment of Tumor Incidences 133 Tissue/Bio-bank Containing Canine/Feline Tumor Samples (Fresh Frozen, FFPE) for Necessary Re-valuation, and Further Testing 133 Comparative Testing of Genetic/Proteomic Tumor Markers on Different Tumor Tissue from Human and Animal Patients 134

8.3 Spontaneous Animal Tumors as Suitable Models for Human Cancers 134

8.3.1 Canine Tumors 134

8.3.2 Feline Tumors 134

8.4 The Swiss Canine/Feline Cancer Registry 1955–2008 135

8.4.1 Swiss Canine Cancer Registry 1955–2008 135 Tumor Location 135 Malignancy of the Most Common Tumor Diagnoses 136 Sex Distribution 136 Breed Distribution 138 Sample Catchment Area 140

8.4.2 The Swiss Feline Cancer Registry 1964–2008 140 Malignancy of the Most Common Tumor Diagnoses 141 Breed Distribution 141 Sex Distribution 142 Most Common Locations of Tumors (1%) 144 Catchment Area 144

8.4.3 Comparison of Swiss Canine, Feline, and Human Cancer Registry Data 146

8.4.4 Conclusion 147

References 148

9 Dog Models of Naturally Occurring Cancer 153
Joelle M. Fenger, Jennie Lynn Rowell, Isain Zapata, William C. Kisseberth, Cheryl A. London, and Carlos E. Alvarez

9.1 Introduction 153

9.1.1 Animal Models of Human Disease and the Need for Alternatives to the Mouse 153

9.2 Advantages of Spontaneous Cancer Models in Dogs 155

9.2.1 High Level of Evolutionary Conservation with Humans 156

9.2.2 Reduced Heterogeneity within Breeds and Increased Variation across Breeds 157

9.2.3 Potential for Comprehensive Genotyping 163

9.2.4 Understanding Both Somatic and Germline Cancer Genetics 164

9.2.5 Translational Models 169

9.3 Dog Cancer Models 170

9.3.1 Canine Cancer Incidence 170

9.3.2 Genetics of Breed-Specific Cancer Models 177 Lymphoma 177 Osteosarcoma 181

9.4 Preclinical and Veterinary Translational Investigations in Dogs with Cancer 184

9.4.1 Preclinical Investigations in Dogs with Spontaneous Cancer 184

9.4.2 Conduct of Preclinical and Translational Studies in Pet Dogs with Cancer 186

9.4.3 Examples of Successful Preclinical Investigations in Pet Dogs with Cancer 190

9.5 Necessary Developments for Realizing the Potential of Canine Models 196

9.5.1 Epidemiology, Longitudinal Cohorts, Tissue Repositories, and Integrative Genomics 196

9.5.2 Improved Genome Annotation and Development of Key Research Areas 196

9.5.3 Opportunities for Understanding the Complete Biology of Spontaneous Cancers 197

9.5.4 Development of High-Impact Programs in Preclinical Cancer Studies 198

9.6 Key Challenges and Recommendations for Using Canine Models 200

9.6.1 Challenges of Population Structure in Dog Models 200

9.6.2 Recommendations for Optimal Results in Canine Preclinical Research 201

9.7 Conclusions 202

References 203

10 Improving Preclinical Cancer Models: Lessons from Human and Canine Clinical Trials of Metronomic Chemotherapy 223
Guido Bocci, Esther K. Lee, Anthony J. Mutsaers, and Urban Emmenegger

10.1 Introduction: Low-dose Metronomic Chemotherapy 223

10.2 Clinical Trials of Metronomic Chemotherapy 224

10.2.1 Achievements 224

10.2.2 Challenges 225

10.3 Veterinary Metronomic Trials in Pet Dogs with Cancer 227

10.3.1 Adjuvant Treatment 228

10.3.2 First-Line Therapy for Metastatic Disease 229

10.3.3 Biomarker Studies 229

10.3.4 Other Chemotherapy Drug Choices 230

10.3.5 Combination with Targeted Anti-angiogenic Drugs 230

10.3.6 Combining Metronomic and MTD Protocols 231

10.4 Lessons Learned from Clinical Trials: Improving the Predictability of Preclinical Models 231

10.4.1 Pharmacokinetic and Pharmacodynamic Studies in Preclinical Models 231 Pharmacokinetic Preclinical Studies of Metronomic Chemotherapy Regimens 233 Pharmacodynamic Analyses in Preclinical Studies 236

10.4.2 Pharmacogenomics in Animal Models 237

10.4.3 Pharmacoeconomics of Metronomic Chemotherapy 238

10.5 Conclusions 240

Acknowledgements 240

References 240

Index 247

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Author Information

Marianne Martic is a senior assistant at the Transdisciplinary Laboratorium Collegium Helveticum, a joint institution of the Swiss Federal Institute of Technolgy (ETH) and the University of Zurich (UZH). She joined the institution after obtaining her degree at the radiopharmaceutical institute of ETH Zürich, where she has worked on animal experimental protocols in the field of positron emission tomography (PET). Her current research is focused on the systematic reviewing and meta-analysis of preclinical animal experiments.

August Schubiger is a senior fellow at the Transdisciplinary Laboratorium Collegium Helveticum, a joint institution of ETH and UZH. He has been full Professor of Radiopharmacy at the Institute of Pharmaceutical Sciences at ETH Zurich and headed the Center for Radiopharmaceutical Science of the ETH, the Paul Scherrer Institute (PSI) and at the Clinic and Polyclinic for Nuclear Medicine at the UZH until 2010. He is currently involved in the project 'Drug development - significance and predictive value of animal testing'.
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