Genomics Book from C.H.I.P.S.

Genomics in Drug Discovery and Development
by Dimitri Semizarov

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


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


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Genomics in Drug Discovery and Development
by Dimitri Semizarov
2009 • 457 pages • $114.00 + shipping
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