Animal Models for Human Cancer

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 Zurich, 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'.

• List of Contributors XIPreface XVA Personal Foreword XVII1 Introduction 1Marianne Isabelle Martic-Kehl, Michael F.W. Festing, Carlos Alvarez, and P. August Schubiger1.1 Animal Models in Biomedical Research 11.2 Animals in the Drug Development Process: Historic Background 21.3 Problems with Translation of Animal Data to the Clinic 51.4 Animal Studies in Anti-cancer Drug Development 61.5 Toward Relevant Animal Data 71.6 Aim of the Book 8References 82 Ethical Aspects of the Use of Animals in Translational Research 11Karin Blumer2.1 Introduction 112.2 Today’s R&D Environment 112.2.1 Four Emerging Trends Shaping Today’s Debate 132.2.1.1 Growing Lack of Awareness of the Nature of Science and Research 132.2.1.2 Increased Pressure on Basic Research 142.2.1.3 Pressure to Assign “Special” Animals a Special Moral and Legal Status 152.2.1.4 A Reductionist Approach to the 3Rs 162.2.2 Preliminary Conclusions 172.3 “Do No Harm”: the Essential Dilemma of Animal Research 172.4 Man and Animals in Philosophy: an Overview of Key Concepts 182.4.1 Anthropocentrism 192.4.2 Physiocentric Positions 192.4.2.1 Holistic Concepts 192.4.2.2 Radical Biocentrism 202.4.2.3 Pathocentrism 212.4.2.4 Moderate Biocentrism 222.5 Conclusions: Solving the Dilemma 23References 243 Study Design 27Michael F.W. Festing3.1 Introduction 273.2 Design Principles 283.3 Experimental Design 283.3.1 The Five Characteristics of aWell-Designed Experiment 293.3.2 The Determination of Sample Size 343.3.2.1 Power Analysis for the Determination of Sample Size 343.3.2.2 The Resource Equation Method of Determining Sample Size 363.3.3 Formal Experimental Designs 363.4 Conclusion 39References 394 Improving External Validity of Experimental Animal Data 41S. Helene Richter, Chiara Spinello, and Simone Macrì4.1 Introduction 414.1.1 Individual Phenotype Is the Result of Genetic and Environmental Influences 414.1.2 Why Do Living Organisms Vary? 424.2 Variation in the Laboratory 434.2.1 How Is Inter-individual Variability Generally DealtWith? 434.2.1.1 Genetic Standardization 444.2.1.2 Environmental Standardization 444.2.1.3 Standardization of the Test Situation 464.3 The Fallacies 464.3.1 The Standardization Fallacy 464.3.2 The Developmental Match Fallacy 474.4 Future Perspectives: an Experimental Strategy Integrating Adaptive Plasticity and Fundamental Methodology 484.4.1 AWay Out of the Standardization Fallacy? 484.4.2 Favoring Adaptive Plasticity through the Provision of Test Strategies Matching Developmental Cues 53References 555 How to End Selective Reporting in Animal Research 61Gerben ter Riet and Lex M. Bouter5.1 Introduction 615.2 Definition and Different Manifestations of Reporting Bias 635.3 Magnitude of Reporting Biases 635.4 Consequences 655.4.1 Consequences of Reporting Bias in Human Randomized Trials 655.4.2 Consequences of Reporting Bias in Experimental Animal Research 665.5 Causes of Reporting Bias 665.6 Solutions 68References 736 A Comprehensive Overview of MouseModels in Oncology 79Divya Vats6.1 Introduction 796.2 Xenograft Mouse Models 816.2.1 Cell-Line Xenograft Model 816.2.2 Patient-derived Xenografts 826.3 Genetically Engineered Mouse Models 836.3.1 Limitations 856.3.2 Chemical Carcinogenesis: N-ethyl-N-nitrosourea Mutagenesis 866.3.2.1 Alkylnitrosamide Compounds 866.3.3 Generation of a Transgenic Mouse Using Pronuclear Injections: Direct Insertion of DNA into Fertilized Zygote 876.3.4 Gene Targeting via Homologous Recombination in Embryonic Stem Cells: Gene Knockouts and Knock-Ins 876.3.5 Conditional Inactivation (or Activation) of Genes 896.3.6 Inducible Systems for Gene Targeting 906.3.7 RNA Interference for Gene Knockdown 926.4 Applications for GEMMs in Compound Development 936.4.1 Target Validation and Compound Testing 936.4.2 Chemoresistance and Toxicity 946.4.3 In vivo Imaging 946.5 Humanized Mouse Models: toward a More Predictive Preclinical Mouse Model 956.6 Conclusions: Potentials, Limitations, and Future Directions for Mouse Models in Cancer Drug Development 986.6.1 Potentials and Limitations 986.6.2 Future Directions 100References 1017 Mouse Models of Advanced Spontaneous Metastasis for Experimental Therapeutics 109Karla Parra, Irving Miramontes, Giulio Francia, and Robert S. Kerbel7.1 Mouse Tumor Models in Cancer Research 1097.2 The Evolution of Metronomic Chemotherapy 1107.3 Development of Highly Aggressive and Spontaneously Metastatic Breast Cancer Models 1127.4 IsThere Any Evidence that Models of Advanced Metastatic Disease Have the Potential to Improve Predicting Future Outcomes of a GivenTherapy in Patients? 1137.5 Metronomic Chemotherapy Evaluation in Preclinical Metastasis Models 1167.6 ExperimentalTherapeutics Using Metastatic Her-2 Positive Breast Cancer Xenografts Models 1167.7 Examples of Recently Developed Orthotopic Models of Human Cancers 1197.8 Factors that Can Affect the Usefulness of Preclinical Models in Evaluating NewTherapies 1207.9 Monitoring Metastatic Disease Progression in Preclinical Models 1207.10 Alternative Preclinical Models: PDX and GEMMs 1217.11 Recommendations for the Evaluation of Anti-cancer Drugs Using Preclinical Models 1227.12 Summary 123References 1248 Spontaneous Animal Tumor Models 129Andreas Pospischil, Katrin Grüntzig, Ramona Graf, and Gianluca Boo8.1 Introduction 1298.2 Advantages of Spontaneous Canine/Feline Cancer Registries 1308.2.1 Effective and Relevant Canine/Feline Cancer Registries – Necessary Steps and Existing Registries 1318.2.1.1 Regional/National/International Population-based Human Cancer Registry with Sufficient Case Numbers and Patient Data 1318.2.1.2 Regional/National Population-based Canine/Feline Cancer Registries 1328.2.1.3 Comparative (Human/Canine/Feline) Geographic and Environmental Risk Assessment of Tumor Incidences 1338.2.1.4 Tissue/Bio-bank Containing Canine/Feline Tumor Samples (Fresh Frozen, FFPE) for Necessary Re-valuation, and Further Testing 1338.2.1.5 Comparative Testing of Genetic/Proteomic Tumor Markers on Different Tumor Tissue from Human and Animal Patients 1348.3 Spontaneous Animal Tumors as Suitable Models for Human Cancers 1348.3.1 Canine Tumors 1348.3.2 Feline Tumors 1348.4 The Swiss Canine/Feline Cancer Registry 1955–2008 1358.4.1 Swiss Canine Cancer Registry 1955–2008 1358.4.1.1 Tumor Location 1358.4.1.2 Malignancy of the Most Common Tumor Diagnoses 1368.4.1.3 Sex Distribution 1368.4.1.4 Breed Distribution 1388.4.1.5 Sample Catchment Area 1408.4.2 The Swiss Feline Cancer Registry 1964–2008 1408.4.2.1 Malignancy of the Most Common Tumor Diagnoses 1418.4.2.2 Breed Distribution 1418.4.2.3 Sex Distribution 1428.4.2.4 Most Common Locations of Tumors (1%) 1448.4.2.5 Catchment Area 1448.4.3 Comparison of Swiss Canine, Feline, and Human Cancer Registry Data 1468.4.4 Conclusion 147References 1489 Dog Models of Naturally Occurring Cancer 153Joelle M. Fenger, Jennie Lynn Rowell, Isain Zapata, William C. Kisseberth, Cheryl A. London, and Carlos E. Alvarez9.1 Introduction 1539.1.1 Animal Models of Human Disease and the Need for Alternatives to the Mouse 1539.2 Advantages of Spontaneous Cancer Models in Dogs 1559.2.1 High Level of Evolutionary Conservation with Humans 1569.2.2 Reduced Heterogeneity within Breeds and Increased Variation across Breeds 1579.2.3 Potential for Comprehensive Genotyping 1639.2.4 Understanding Both Somatic and Germline Cancer Genetics 1649.2.5 Translational Models 1699.3 Dog Cancer Models 1709.3.1 Canine Cancer Incidence 1709.3.2 Genetics of Breed-Specific Cancer Models 1779.3.2.1 Lymphoma 1779.3.2.2 Osteosarcoma 1819.4 Preclinical and Veterinary Translational Investigations in Dogs with Cancer 1849.4.1 Preclinical Investigations in Dogs with Spontaneous Cancer 1849.4.2 Conduct of Preclinical and Translational Studies in Pet Dogs with Cancer 1869.4.3 Examples of Successful Preclinical Investigations in Pet Dogs with Cancer 1909.5 Necessary Developments for Realizing the Potential of Canine Models 1969.5.1 Epidemiology, Longitudinal Cohorts, Tissue Repositories, and Integrative Genomics 1969.5.2 Improved Genome Annotation and Development of Key Research Areas 1969.5.3 Opportunities for Understanding the Complete Biology of Spontaneous Cancers 1979.5.4 Development of High-Impact Programs in Preclinical Cancer Studies 1989.6 Key Challenges and Recommendations for Using Canine Models 2009.6.1 Challenges of Population Structure in Dog Models 2009.6.2 Recommendations for Optimal Results in Canine Preclinical Research 2019.7 Conclusions 202References 20310 Improving Preclinical Cancer Models: Lessons from Human and Canine Clinical Trials of Metronomic Chemotherapy 223Guido Bocci, Esther K. Lee, Anthony J. Mutsaers, and Urban Emmenegger10.1 Introduction: Low-dose Metronomic Chemotherapy 22310.2 Clinical Trials of Metronomic Chemotherapy 22410.2.1 Achievements 22410.2.2 Challenges 22510.3 Veterinary Metronomic Trials in Pet Dogs with Cancer 22710.3.1 Adjuvant Treatment 22810.3.2 First-Line Therapy for Metastatic Disease 22910.3.3 Biomarker Studies 22910.3.4 Other Chemotherapy Drug Choices 23010.3.5 Combination with Targeted Anti-angiogenic Drugs 23010.3.6 Combining Metronomic and MTD Protocols 23110.4 Lessons Learned from Clinical Trials: Improving the Predictability of Preclinical Models 23110.4.1 Pharmacokinetic and Pharmacodynamic Studies in Preclinical Models 23110.4.1.1 Pharmacokinetic Preclinical Studies of Metronomic Chemotherapy Regimens 23310.4.1.2 Pharmacodynamic Analyses in Preclinical Studies 23610.4.2 Pharmacogenomics in Animal Models 23710.4.3 Pharmacoeconomics of Metronomic Chemotherapy 23810.5 Conclusions 240Acknowledgements 240References 240Index 247