Genomics in Drug Discovery and Development

New, effective strategies for early assessment of drug toxicity and efficacy
Genomics in Drug Discovery and Development introduces readers to the biomarker, pharmacogenomic, pharmacogenetic, and toxicogenomic toolboxes, four promising and rapidly growing areas of genomics research that have begun opening the door to personalized medicine solutions. The authors thoroughly review and analyze all relevant technologies and analytical methods necessary for the competent design and execution of biomarker, pharmacogenomic, pharmacogenetic, and toxicogenomic studies. Moreover, by emphasizing the synergies among these areas, they arm pharmaceutical discovery scientists and drug development professionals with state–of–the–art strategies for reducing drug development time and costs, expediting a drug′s approval, and improving its life cycle. Academic researchers will find in this book authoritative and integrated coverage of these rapidly developing and popular areas of genomic research.
Readers involved in laboratory, clinical, or modeling studies who are seeking to assess the toxicity and efficacy of drug candidates as early as possible can rely on this book to help guide their experiments. Topics include:
Weighing the relative advantages and disadvantages of available genomic technology platforms
Using pharmacogenomics and pharmacogenetics to position drug studies in the context of clinical trials
Identifying and validating biomarkers
Predicting and characterizing the toxicity of drugs
Applying study findings to improve the productivity of drug discovery
Today′s pharmaceutical industry is characterized by exponentially rising R&D costs and a steadily decreasing percentage of approved drugs. Pharmaceutical discovery scientists therefore should take advantage of this book′s unique integrated coverage of biomarkers, toxicogenomics, and pharmacogenomics in order to make thei r own discovery efforts as fruitful as possible.

Spis treści:
Preface.
Chapter 1: Introduction: Genomics and Personalized Medicine (Dimitri Semizarov).
1.1. Fundamentals of genomics.
1.2. The concept of personalized medicine.
1.3. Genomics technologies in drug discovery.
1.4. Scope of this book.
References.
Chapter 2: Genomics Technologies as Tools in Drug Discovery (Dimitri Semizarov).
2.1. Introduction to genomics technologies.
2.2. Gene expression microarrays: technology.
2.2.1. Standard microarray protocol.
2.2.2. Monitoring the quality of RNA for microarray experiments.
2.2.3. Specialized microarray protocols for archived and small samples.
2.2.4. Quality of microarray data and technical parameters of microarrays.
2.2.5. Reproducibility of expression microarrays and cross–platform comparisons.
2.2.6. Microarray databases and annotation of microarray data.
2.3. Gene expression microarrays: data analysis.
2.3.1. Identification of significant gene expression changes.
2.3.2. Sample classification and class prediction using expression microarrays.
2.3.3. Pathway analysis with gene expression microarrays.
2.3.4. Common problems affecting the validity of microarray studies.
2.4. Comparative genomic hybridization: technology.
2.5. Comparative genomic hybridization: data analysis.
2.6. Microarray–based DNA methylation profiling.
2.7. Microarray–based microRNA profiling.
2.8. Technical issues in genomics experiments and regulatory submissions of microarray data.
2.8.1. Study of a drug’s mechanism of action by gene expression profiling.
2.8.2. Early assessment of drug toxicity in model systems.
2.8.3. Biomarker identification in discovery and early development.
2.8.4. Patient stratification in clinical trials using gene expression signatures.
2.8.5. Genotyping of patients in clinical studies to predict drug response.
2.9 . Conclusion.
References.
Chapter 3: Genomic Biomarkers (Dimitri Semizarov).
3.1. Introduction into genomic biomarkers.
3.2. DNA biomarkers.
3.2.1. DNA copy number alterations.
3.2.1.1. DNA copy alterations in cancer.
3.2.1.2. DNA copy number alterations in other diseases.
3.2.1.3. Identification of DNA copy number biomarkers in drug discovery.
3.2.2. Mutations.
3.2.2.1. p53 mutations.
3.2.2.2. K–ras mutations.
3.2.2.3. EGFR mutations.
3.2.2.4. Bcr–abl and KIT mutations.
3.2.3. Epigenetic markers.
3.3. RNA biomarkers.
3.3.1. Gene expression biomarkers validated as diagnostic tests.
3.3.2. Other examples of gene expression biomarkers.
3.4. Clinical validation of genomic biomarkers.
References.
Chapter 4: Fundamental Principles of Toxicogenomics (Eric Blomme).
4.1. Introduction.
4.2. Fundamentals of toxicogenomics.
4.2.1. Principle of toxicogenomics.
4.2.2. Technical reproducibility.
4.2.3. Biological reproducibility.
4.2.4. Species extrapolation.
4.3. Analysis of toxicogenomics data.
4.3.1. Compound–induced gene expression changes.
4.3.2. Visualization tools.
4.3.3. Class prediction.
4.3.4. Network and pathway analysis.
4.4. Practical and logistic aspects of toxicogenomics.
4.4.1. Species considerations.
4.4.2. Toxicogenomics studies.
4.4.2.1. Sample considerations.
4.4.2.2. Experimental design in toxicogenomics studies.
4.5. Toxicogenomics reference databases.
4.5.1. The utility of reference databases in toxicogenomics.
4.5.2. Design and development of toxicogenomics reference databases.
4.5.3. Existing toxicogenomics databases.
4.6. Conclusion.
References.
Chapter 5: Toxicogenomics: Applications to In Vivo Toxicology (Eric Blomme).
5.1. The value of toxicogenomics in drug discovery and development.
5.2. Basic principles of toxicology in drug discovery and development.
5.2.1. Preclinica l safety assessment.
5.2.2. Discovery toxicology.
5.3. Toxicogenomics in predictive toxicology.
5.3.1. Prediction of hepatotoxicity.
5.3.2. Prediction of nephrotoxicity.
5.3.3. Prediction of in vivo carcinogenicity.
5.3.4. Gene expression–based biomarkers in other tissues and the promise of hemogenomics.
5.3.5. Integration of toxicogenomics in discovery toxicogology.
5.4. Toxicogenomics in mechanistic toxicology.
5.4.1. Toxicogenomics to investigate mechanisms of hepatotoxicity.
5.4.2. Intestinal toxicity and Notch signaling.
5.4.3. Cardiac toxicity.
5.4.4. Testicular toxicity.
5.5. Toxicogenomics and target–related toxicity.
5.5.1. Target expression in normal tissues.
5.5.2. Target modulation.
5.6. Predicting species–specific toxicity.
5.7. Evaluation of idiosyncratic toxicity with toxicogenomics.
5.8. Conclusion.
References.
Chapter 6: Toxicogenomics: Applications in In Vitro Systems (Eric Blomme).
6.1. Introductory remarks on in vitro toxicology.
6.2. Overview of the current approaches to in vitro toxicology.
6.3. Toxicogenomics in in vitro systems: technical considerations.
6.3.1. Reproducibility.
6.3.2. Genomic classifiers.
6.3.3. Testing concentrations.
6.3.4. Throughput and cost.
6.4. Proof–of–concept studies using primary rat hepatocytes.
6.5. Use of gene expression profiling to assess genotoxicity.
6.5.1. Toxicogenomics can differentiate genotoxic carcinogens from non–genotoxic carcinogens.
6.5.2. Toxicogenomics can differentiate DNA reactive from non–DNA reactive compounds positive in the in vitro mammalian cell–based genotoxicity assays.
6.5.3. Toxicogenomics assays may be less sensitive than the standard battery of in vitro genetic toxicity tests.
6.6. Application of gene expression profiling for the in vitro detection of phopholipidosis.
6.7. Toxicog