Principles of Translational Science in Medicine: From Bench to Bedside

Principles of Translational Science in Medicine
Copyright
Contents
List of contributors
1 Introduction and definitions
	What is translational medicine?
	Primary translation versus secondary translation
	The history of translational medicine, obstacles, and remits
	References
2 Problems, challenges, and initiatives in translation
	Attrition
	What translational medicine can and cannot do
	The present status of translational medicine (initiatives and deficiencies)
		New pathways to discovery
		Research teams of the future
		Reengineering the clinical research enterprise
	Translational science in medicine: the current challenge
	References
3 “Omics” translation: a challenge for laboratory medicine
	Introduction
	“Omics”: what does it mean?
	Proteomics as a paradigm of problems in translational medicine
	Development of biomarkers: from discovery to clinical application
	Discovery
	Identification/characterization
	Validation
	Standardization/harmonization
	Clinical association and clinical benefit
	Translating omics into clinical practice
	Continuum of translation research and omics
	Conclusions
	References
4 The power of genomics, metabolomics, and other omics for target identification and validation
	Introduction
	Genomics
		Genomic tools
			Sequencing
				Sequencing by ligation
				Sequencing by synthesis
			Arrays
				Oligonucleotide microarrays
				cDNA microarrays
			Quantitative reverse transcription polymerase chain reaction and low-density arrays
		Applications of genomics in molecular medicine
			Molecular diagnostics
			Pharmacogenomics
	Metabolomics
		Metabolomics or metabonomics?
			Metabolite profiling
			Metabolite fingerprinting
			Metabolic footprinting
		Analytical techniques in metabolomics/metabonomics
			Nuclear magnetic resonance
			Mass spectrometry
		Omics and biomarkers
		Metabolomics and metabonomics in clinical use
	Conclusion
	References
5 Potency analysis of cellular therapies: the role of molecular assays
	Introduction
	Potency testing
	Complexities associated with potency testing of cellular therapies
	Factors affecting the potency of cellular therapies
	Measuring potency of cellular therapies
	Gene expression arrays for potency testing
	Potential applications of gene expression profiling for potency testing
		Predicting the confluence of human embryonic kidney 293 cells
		Cell differentiation status analysis of embryonic stem cells
		Potency testing of hematopoietic stem cells
		Potency testing of dendritic cells
		Cultured CD4+ cells
		Bone marrow stromal cell
		CAR T cells
	MicroRNAs as potency assays
	Conclusions
	References
6 Translational pharmacogenetics: pharmacogenetically driven clinical decision making
	Introduction
	Pharmacogenetics as a tool for improving individual drug therapy
	Types of drug therapies that might profit from pharmacogenetic diagnostics
	The status of translational pharmacogenetics in various drug therapy fields
		Depression
		Cardiovascular disease
			Beta blockers
			Vitamin K antagonists
			Statins and proton pump inhibitors
		Pain treatment
		Malignant diseases
			Tamoxifen
			Thiopurines
			5-Fluorouracil
			Irinotecan
	Translational pharmacogenetics and the need for clinical studies to support pharmacogenetically driven prescribing
	References
7 Tissue biobanks
	Introduction
	The concept of biobanking
		Population-oriented biobanks
		Disease-oriented biobanks
		Virtual biobanks
		Biobanking for research
		Biobanking for clinical use
	Types of biospecimens
		Tissue
		Body fluids
		Cellular models
		Nucleic acids: DNA and RNA
		Protein and other subcellular components
		Quality assurance of biospecimens
	Biobanking in the era of precision medicine
	Ethical issues
	References
8 Animal models: value and translational potency
	What is the value of animal models? Pathophysiological concepts
	What is a good animal model for translational research?
		Modeling comorbidities
		Modeling care of patients
	What is the translational value of animal models?
	Remedies for failed translation: improving preclinical research
		Improving models
		Improve rigor of preclinical studies
	Summary
	References
9 Biomarkers in the context of health authorities and consortia
	Introduction
	From biomarkers to diagnostic tests to improve patient care
	In vitro diagnostic tests
		In vitro diagnostic tests and US regulations
		In vitro diagnostic tests and Europe regulations
	Companion diagnostics
	Lab tests (CLIA test or lab-developed test)
	Drug development tools
		The critical path initiative
		New regulatory pathways for qualification of biomarkers and drug development tools
		Examples
	Collaborations for biomarkers and drug development tools
		Public-private partnerships (cooperative R&D agreements)
		Consortia
			The Critical Path Institute’s Predictive Safety Testing Consortium
			The innovative medicines initiative in Europe
			The PhRMA Biomarkers Consortium
	References
10 Human studies as a source of target information
	Using old drugs for new purposes: baclofen
	Serendipity: sildenafil
	Reverse pharmacology
	References
11 Target profiling in terms of translatability and early translation planning
	Essential dimensions of early translational assessment
	A translatability scoring instrument: risk balancing of portfolios and project improvement
	Case studies: applying the translatability scoring instrument to real-life experiences
	References
12 Biomarkers
	Defining biomarkers as very important contributors to translational science
	Classes of biomarkers
	Development of biomarkers
	Predictivity classification of biomarkers and scores
	Case studies
	References
13 Genetics, molecular biomarkers, and artificial intelligence to improve diagnostic and prognostic efficacy
	Introduction
	Source of errors in clinical proteomics studies
	Source of errors in next-generation sequencing
	Bioinformatics and computational tools for clinical proteomic studies
	Bioinformatics and computational tools for next-generation sequencing
		Artificial intelligence, machine learning, and deep learning techniques to improve the clinical utility of clinical proteom...
		Machine learning: supervised and unsupervised learning
		Techniques to avoid overfitting issues
	Examples of the applications of genetics and molecular markers for diagnostic or prognostic purposes
		Ovarian cancer
			Genetic studies
		Prostate cancer
			Genetics studies
		Pancreatic cancer
			Machine learning-derived biomarkers
			Genetics studies
	Conclusions
	References
14 Cardiovascular translational biomarkers: translational aspects of hypertension, atherosclerosis, and heart failure in dr...
	What is new?
	Hypertension
		Introduction
		Animal models of hypertension
		Biomarkers of hypertension
		Blood-borne biomarkers
			Renin-angiotensin-aldosterone system and sympathetic-adrenergic system activity
		Endothelial dysfunction
			Markers of vascular resistance
			Markers of inflammation
			Markers of coagulation
			MicroRNAs and genetic variants
	Digital biomarkers of hypertension
	Atherosclerosis
		Introduction
	Animal models of atherosclerosis
		Biomarkers for atherosclerosis
	Imaging (digital) biomarkers in atherosclerosis conditions
	Continuously measured digital biomarkers in atherosclerosis conditions
	Heart failure
		Introduction
	Animal models in heart failure
		Valvular lesions
		Dilated cardiomyopathies
		Genetically driven heart failure models
		Ischemic heart failure models
	Traditional biomarkers of heart failure
	Soluble markers for cardiac remodeling and fibrosis
	Soluble markers for myocardial stretch
	Markers of inflammation
	Digital biomarkers of heart failure
	Cardiovascular biomarkers: Quo Vadis?
	Case study: atrial fibrillation
	Conclusion
	References
15 Biomarkers in oncology
	Circulating biomarkers
	Pharmacodynamic markers: target inhibition
	Focus on lung cancer
	The PD-1/PD-L1 axis
	Conclusion
	References
16 Translational medicine in psychiatry: challenges and imaging biomarkers
	Biological treatment of psychiatric disorders
	Specific challenges of translation in psychiatry
		Unknown pathophysiology
		Stigma and the second translation
	New biomarkers for translation in psychiatry
	Imaging biomarkers in schizophrenia
		Structural brain biomarkers
		Functional imaging markers in schizophrenia
		Auditory and language processing
		Motor functioning
		Working memory
		Selective attention
	Imaging of genetic susceptibility factors
	Characterization of antipsychotic drug effects
	Multiomics and transdiagnostic biomarker discovery
	Conclusions and future directions
	References
17 Methodological studies
	Conventional phase I trial methodology
		Aims
		Design
		Patient entry criteria
			Performance status
			Cancer type
			Laboratory investigations within appropriate limits as entry criteria
		Special drug administration or procedures
		Patient consent
		Calculation of the starting dose
		Dose escalation
		Number of patients required for dose administration
		Stopping rules
	Measuring endpoints
		Toxicity
		Pharmacodynamic endpoints
	Mechanism-oriented trial design
		Proof-of-mechanism
		Proof-of-principle
		Proof-of-concept
	Can we make go-or-no-go decisions at the end of phase I?
	Phase II trials
	Personalized medicine
	The contribution of modern imaging to early-phase trials
	Anatomical and molecular imaging evaluation
	Metabolic measurements using positron emission tomography ligands
	Choice of imaging modality
	Radiomics
	Quantification imaging methods
	The role of imaging in phase I trials
	Challenges for novel imaging methodologies and clinical trials
	Conclusion
	Open access clinical trials
	References
18 The pharmaceutical research and development productivity crisis: can exploratory clinical studies be of any help?
	Traditional drug development
	Definition of exploratory clinical studies
	Decision making: regulatory perspective versus company internal perspective in phase I and phase IIa
	The problem at hand: attrition versus opportunity focus
	From phase thinking to question-based development
		Does the biologically active compound or active metabolites get to the site of action?
		Does the compound cause its intended pharmacological/functional effect(s)?
		Does the compound have beneficial effects on the disease or its pathophysiology?
		What is the therapeutic window of the new drug?
		How do the sources of variability in drug response in the target population affect the development of the product?
	High risk and variable costs: how to address the risk-cost combination in development?
	Real options in translational development
	Exploratory studies: the scorn perspective
	Exploratory studies: the value perspective
	Summary: challenges and outlook
	References
19 Adaptive trial design
	References
20 Combining regulatory and exploratory trials
	References
21 Accelerating proof of concept by smart early clinical trials
	References
22 Pharmaceutical toxicology
	Introduction
	Discovery toxicology
		Target
		Chemistry
		Patient
	Regulatory toxicology
		Historical context
		Good laboratory practice
		The goals of regulatory toxicology
		Dose-response relationships
		Translational considerations and context
		Animal models and future perspectives
		Alternative approaches in regulatory toxicology: the exploratory investigational new drug approach
		Biomarkers
		Preclinical safety from a translational perspective
	References
23 Translational safety medicine
	Introduction
	State of affairs of translational safety medicine
	Constraints to effective translational safety medicine
		The broken safety value chain
		The conceptual approach to safety
		The nature of safety work
		Organizational structure
	Practicing translational safety medicine
		Organizational setup
			The safety management team
			Safety governance
			Conflict resolution
			Safety strategy
			Recording safety information and strategy
			Safety strategy document
			Constant 360-degree vigilance
			Preparing for the unexpected
			Practical aspects
				Test substance
				Dose
				Exposure
				Effect
	In summary
		Translational safety future
			Creating a digital memory
			Changes in sampling
			Pharmacokinetics sampling
			Safety and efficacy biomarker monitoring
			Monitoring disease state
			Improved monitoring of known safety biomarkers
			Detecting previously nonquantifiable tolerability
			Identifying the right population
			Embracing data
			Understanding tolerability
			Summary: looking to the future
	References
24 Cancer vaccines: translational strategies
	Introduction
	Historic perspective of immune system involvement in the biology of cancer
		Spontaneous regression
		Abscopal response
	Microbes: the first cancer vaccine platform in the history of modern medicine
	Discovery of cytokines and the first usage in cancer treatment
	Discovery of white blood cell subtypes and translation from bench to bed
	Nucleic acid–based cancer vaccines
	Synthetic peptides as a cancer vaccine
	Medical advances with monoclonal antibodies in clinical fields
	Virus-based cancer vaccine platforms
	Neoepitope vaccines
	Combination strategies
	Cancer vaccines with broader goals
		Vaccines targeting the tumor microenvironment
		Vaccines with preventive or adjuvant purposes
	Challenges and future directions
	Conclusion
	References
25 Translational aspects of biologicals: monoclonal antibodies and antibody-drug conjugates as examples
	Overview of monoclonal antibodies for cancer therapy
	Structure and functions of antibodies
	Generation of monoclonal antibodies for cancer therapy
	Mechanisms of action of antibodies for cancer therapy
		Fab-mediated mechanisms of antibodies for cancer therapy
		Fc-mediated mechanisms of antibodies for cancer therapy
		Engaging the adaptive immune response
		Engaging antitumor immune responses via checkpoint blockade
		Harnessing IgE-mediated immune surveillance against cancer cells
	Antibody-drug conjugates
		Mechanism of action of antibody-drug conjugates
		Antibody-drug conjugates in preclinical development and clinical use
			Trastuzumab emtansine
			Examples of target antigens for antibody-drug conjugates in preclinical and clinical development
				Epidermal growth factor receptor as a potential antigen for antibody-drug conjugate therapy
				Folate receptor alpha as a potential antigen for antibody and antibody-drug conjugate therapy
		Choice of antibody
			Importance of the antibody Fc region
		Choice of linker
		Choice of cytotoxic payload
		Challenges in antibody-drug conjugate design, evaluation and translation
	Conclusion
	Acknowledgments
	References
26 Orphan drugs: why is translation so successful?
	Introduction
	Special characteristics of translational processes for orphan drugs
	References
27 Translational science biostatistics
	Statistical problems in translational science
	Statistical models and statistical inference
	Design and interpretation of an experiment
	Multiplicity
	Biomarkers
	Biological modeling
		Example 1: pharmacodynamics
		Example 2: pharmacokinetics
	Statistical models
	References
28 Computational biology and model-based approaches in translational medicine
	Introduction: Model building in sciences
		Compartmental modeling of pharmacokinetics: A conceptual framework for translational applications in clinical pharmacology
		Physiologically based modeling: prediction of pharmacokinetics in children
		Blood coagulation modeling: Prediction of pharmacodynamic drug interactions
	Model-informed drug development and discovery (MID3)
	References
29 Intellectual property and innovation in translational medicine
	Introduction
	Context
		General description of translational medicine
		Intellectual property and translational medicine
			Basic functioning of patents4
			Importance of the patent system
		Open science
			Definition and principles
			Benefits of open science
			Renewed interest in open science
		Open innovation
			Definition and objectives
			Benefits of open innovation
		Public-private partnership models
			Definition and objectives
			Benefits of public-private partnership models
	Trends in translational intellectual property
		Patents and research tools
		Patents on genetic tests and personalized therapies
			Genetic tests
			Personalized therapies
		Patents on risk prediction models
		Patents on new and repositioned drugs
		3D bioprinters
		Secrecy
	Discussion
		A perspective on the future of genetic patents
			Patentability of gene sequences
			Patenting of gene sequences and promotion of innovation
			Patenting of gene sequences and access to healthcare
		Trade secrecy as an option alternative to patents
		Toward balanced innovation environment
	Conclusion
	Acknowledgments
	References
30 Translational research in the fastest-growing population: older adults
	Introduction
		Why study aging?
		Lifespan versus healthspan
	Translational aging research
		Using a geroscience approach
		Biology of aging: hallmarks, pillars, and health
			Damage accumulation over time
			Failure of endogenous repair mechanisms
			Higher-order consequences of damage
		From biological mechanisms to clinical aging phenotypes
		Animal models in translational aging research
		Human approaches to translational aging research
	Testing treatments to extend healthspan and lifespan
		Clinical trials in geroscience
		Outcomes for clinical trials testing geroscience-inspired interventions
		Limitations for both animal and human models
	Examples of experimental therapies in aging research
		Caloric restriction and intermittent fasting
		Experimental therapies targeting cellular senescence
			Dasatinib + quercetin
			Fisetin
			BCL and MDM2 pathway inhibitors
			Senolytic drug trials
	Translational aging resources
		Animals and animal tissues
		Cohorts and populations
		Tools and toolboxes
	Conclusion
	References
31 Translational medicine: the changing role of big pharma
	Introduction
	History: how did we get here?
		Biotech: the big disruptor
		Expansion of the biotech sector
	Academia and integrated discovery nexuses
	Pharma meets academia: models of external innovation
	Precompetitive consortia
	Attitudes, ethics, and standards
	Coronavirus and the road ahead
	References
32 Translational science in medicine: putting the pieces together-biomarkers, early human trials, networking, and translata...
	References
33 Learning by experience
	Example of a smart, successful translational process
	Example of a failed translational process
	References
Index