Genomics in Drug Discovery and Development introduces readers to the biomarker, pharmacogenomic, and toxicogenomics toolbox.

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

Genomics in Drug Discovery and Development

Contents

1. Genomics and personalized medicine

• Fundamentals of genomics
• The concept of personalized medicine
• Genomics technologies in drug discovery
• Scope of this book

2. Genomics technologies as tools in drug discovery

• Gene expression microarrays: technology
• Standard microarray protocol
• Monitoring the quality of RNA for microarray experiments
• Specialized microarray protocols for archived and small samples
• Quality of microarray data and technical parameters of microarrays
• Reproducibility of expression microarrays and cross-platform comparisons
• Microarray databases and annotation of microarray data
• Gene expression microarrays: data analysis
• Identification of significant gene expression changes
• Sample classification and class prediction using expression microarrays
• Pathway analysis with gene expression microarrays
• Common problems affecting the validity of microarray studies
• Comparative genomic hybridization: technology
• Comparative genomic hybridization: data analysis
• Microarray-based DNA methylation profiling
• Microarray-based microRNA profiling
• Technical issues in genomics experiments and regulatory submissions of microarray data
• Study of a drug’s mechanism of action by gene expression profiling
• Early assessment of drug toxicity in model systems
• Biomarker identification in discovery and early development
• Patient stratification in clinical trials using gene expression signatures
• Genotyping of patients in clinical studies to predict drug response

3. Genomic biomarkers

• DNA biomarkers
• DNA copy number alterations
• DNA copy alterations in cancer
• DNA copy number alterations in other diseases
• Identification of DNA copy number biomarkers in drug discovery
• Mutations
• p53 mutations
• K-ras mutations
• EGFR mutations
• Bcr-abl and KIT mutations
• Epigenetic markers
• RNA biomarkers
• Gene expression biomarkers validated as diagnostic tests
• Other examples of gene expression biomarkers
• Clinical validation of genomic biomarkers

4. Fundamental principles of toxicogenomics

• Fundamentals of toxicogenomics
• Principle of toxicogenomics
• Technical reproducibility
• Biological reproducibility
• Species extrapolation
• Analysis of toxicogenomics data
• Compound-induced gene expression changes
• Visualization tools
• Class prediction
• Network and pathway analysis
• Practical and logistic aspects of toxicogenomics
• Species considerations
• Toxicogenomics studies
• Sample considerations
• Experimental design in toxicogenomics studies
• Toxicogenomics reference databases
• The utility of reference databases in toxicogenomics
• Design and development of toxicogenomics reference databases
• Existing toxicogenomics databases

5. Toxicogenomics: applications to in vivo toxicology

• The value of toxicogenomics in drug discovery and development
• Basic principles of toxicology in drug discovery and development
• Preclinical safety assessment
• Discovery toxicology
• Toxicogenomics in predictive toxicology
• Prediction of hepatotoxicity
• Prediction of nephrotoxicity
• Prediction of in vivo carcinogenicity
• Gene expression-based biomarkers in other tissues and the promise of hemogenomics
• Integration of toxicogenomics in discovery toxicogology
• Toxicogenomics in mechanistic toxicology
• Toxicogenomics to investigate mechanisms of hepatotoxicity
• Intestinal toxicity and Notch signaling
• Cardiac toxicity
• Testicular toxicity
• Toxicogenomics and target-related toxicity
• Target expression in normal tissues
• Target modulation
• Predicting species-specific toxicity
• Evaluation of idiosyncratic toxicity with toxicogenomics

6. Toxicogenomics: applications in in vitro systems

• Overview of the current approaches to in vitro toxicology
• Toxicogenomics in in vitro systems: technical considerations
• Reproducibility
• Genomic classifiers
• Testing concentrations
• Throughput and cost
• Proof-of-concept studies using primary rat hepatocytes
• Use of gene expression profiling to assess genotoxicity
• Toxicogenomics can differentiate genotoxic carcinogens from non-genotoxic carcinogens
• Toxicogenomics can differentiate DNA reactive from non-DNA reactive compounds positive in the in vitro mammalian cell-based genotoxicity assays
• Toxicogenomics assays may be less sensitive than the standard battery of in vitro genetic toxicity tests
• Application of gene expression profiling for the in vitro detection of phopholipidosis
• Toxicogenomics in the assessment of idiosyncratic hepatotoxicity
• Do peripheral blood mononuclear cells represent a useful alternative in vitro model?
• Current and future use of in vitro toxicogenomics
• Improved gene expression platforms
• Standardization of protocols and experimental approaches
• Performance accuracy
• Battery of gene expression signatures
• Clear actionable data points

7. Germline polymorphisms and drug response

• Polymorphisms and drug response in oncology
• UGT1A1 polymorphism and response to irinotecan
• FGFR4 polymorphism and response to chemotherapy
• Mdr-1 polymorphism and response to paclitaxel
• DPD polymorphisms and response to 5’-fluorouracil
• TPMT variants and response to thiopurines
• MTHFR polymorphisms and response to chemotherapy
• Tandem repeat polymorphisms in the TS gene and response to drugs targeting thymidylate synthase
• Use of cancer cell lines to identify predictive SNPs
• Polymorphisms and response to anticoagulants
• Polymorphisms in neuroscience
• Polymorphisms and drug response in immunology
• Polymorphisms and response to antiviral agents
• Anti-HIV drugs
• Interferon therapy in hepatitis B treatment
• Gene copy number polymorphisms
• Conclusions: approaches to identification of polymorphisms as predictors of drug response
• Candidate gene approach
• Genome-wide approach
• Pathway approach
• Use of model systems in the identification of predictive pharmacogenetic markers
• Comparison of the methodologies in the context of drug discovery

8. Pharmacogenetics of drug disposition

• Genes and polymorphisms affecting drug disposition
• Drug metabolizing enzymes
• Drug transport proteins
• Genomic biomarkers for PK studies
• Utility of PG--PK studies in early clinical trials
• Limitations of PG--PK studies
• Genotyping technologies

9. Overview of regulatory developments and initiatives related to the use of genomic technologies in drug discovery and development

• FDA guidance on pharmacogenomic data submission
• Voluntary genomic data submission (VGDS)
• Pharmacogenomic data submission
• International harmonization
• Pharmacogenomic data submission: draft companion guidance
• Drug-diagnostic co-development concept paper
• Regulations for in vitro diagnostic assays
• General overview of regulatory pathways for devices in the U.S.A.
• Draft guidance for industry, clinical laboratories, and FDA staff on in vitro diagnostic multivariate index assays
• Biomarker qualification
• Current initiatives relevant to pharmacogenomics
• Future impact of genomic data on drug development

Index

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