Molecular Pathology in Drug Discovery and Development

Contributors.

1 MOLECULAR PATHOLOGY AND DRUG DEVELOPMENT (Franz Fogt and J. Suso Platero).

1.1. General Pathology.

1.2. General Aspects.

1.3. Molecular Pathology, the Molecular Way.

1.4. Application of Molecular Pathology.

1.5. Molecular Pathology in Drug Development.

1.6. Pharmaceutical Drug Development.

References.

2 MOLECULAR PATHOLOGY IN ONCOLOGY TARGET AND DRUG DISCOVERY (Rolf-P. Ryseck, Ricardo Attar, Matthew V. Lorenzi, and Brent A. Rupnow).

2.1. Introduction.

2.2. History of Chemotherapy and Cancer Drug Discovery.

2.3. Target-Based Drug Discovery.

2.4. Utilization of Molecular Pathology in the Discovery of Novel Cancer Targets.

2.5. Hit Identifi cation and In Vitro Lead Optimization.

2.6. Implications for Molecular Pathology in Cancer Drug Development and Use.

2.7. Summary and Future Considerations.

References.

3 MOLECULAR PATHOLOGY AND TRANSCRIPTIONAL PROFILING IN EARLY DRUG DEVELOPMENT (Cornelia Liedtke, Lajos Pusztai, and W. Fraser Symmans).

3.1. Introduction.

3.2. Biomarkers in Clinical Setting and in Early Drug Development.

3.3. Advantages of Biomarker Implementation.

3.4. Changing Paradigm in Clinical Drug and Biomarker Development.

3.5. Promises of Transcriptional Profiling.

3.6. Biomarker Development and Validation Using Microarray Analysis.

3.7. Neoadjuvant Chemotherapy as an Intriguing Model for Biomarker Development.

3.8. Transcriptional Profi ling for Identifi cation of Individual Genes as Biomarkers.

3.9. Transcriptional Profi ling for the Definition of Multigene Predictors Using .Transcriptional Profiling.

3.10. Novel Tools for Pathway Analysis.

3.11. Implementation of Biomarkers into the Clinical Setting.

3.12. Conclusion.

References.

4 MOLECULAR PATHOLOGY IN NONCLINICAL SAFETY ASSESSMENT (Richard A. Westhouse).

4.1. Introduction.

4.2. Drug Development.

4.3. Drug Discovery.

4.4. Biopharmaceuticals.

4.5. Summary.

References.

5 TOXICOGENOMICS IN DRUG DEVELOPMENT (Wayne R. Buck and Eric A. G. Blomme).

5.1. Introduction.

5.2. Brief Overview of Large-Scale Gene Expression Technologies.

5.3. Analysis of Microarray Data.

5.4. Application of Toxicogenomics in Drug Development.

5.5. Considerations for Toxicogenomic Study Design.

5.6. Overview of Major Regulatory Developments Related to Use of Toxicogenomics in Drug Discovery and Development.

5.7. Summary.

References.

6 MOLECULAR PATHOLOGY AS A WAY TO FIND THE RIGHT DOSE FOR A DRUG (F. Rojo, A. Rovira, S. Serrano, and J. Albanell).

6.1. Introduction.

6.2. Anti-EGFR-Targeted Therapies: The Pharmacodynamic Experience.

6.3. Molecular Pathology with Small Molecules Gefitinib and Erlotinib.

6.4. Molecular Pathology with Cetuximab and Other Monoclonal Antibodies to EGFR.

6.5. Proteasome Inhibitors: Pharmacodynamics on Blood Samples.

6.6. Pharmacodynamics with Rapamycin Analogs.

6.7. Second Generation of Targeted Therapies: Multitarget Agents.

6.8. Conclusions and Perspectives: Phase 0 Clinical Trials.

References.

7 MOLECULAR PATHOLOGY IN LIFE-CYCLE MANAGEMENT IN DRUG DEVELOPMENT (Martha Quezado, Carlos A. Torres-Cabal, and David Berman).

7.1. Introduction.

7.2. Molecular Pathology Techniques.

7.3. Practical Applications of Molecular Pathology Biomarkers.

7.4. Conclusion.

References.

8 MOLECULAR PATHOLOGY AND MOLECULAR THERAPY (Hewei Li).

8.1. Introduction.

8.2. Molecular Therapy Strategies.

8.3. Molecular Therapy Clinical Trials.

References.

9 MOLECULAR PATHOLOGY: IMMUNOHISTOCHEMISTRY ASSAYS IN DRUG DEVELOPMENT PERFORMED BY A CONTRACT RESEARCH LABORATORY (Frank Lynch and Steve Bernstein).

9.1. Immunohistochemistry Is the Technique of Microscopic Visualization of Target Proteins in Tissue Sections Using Specific Antibodies.

9.2. Basics of the IHC Assay.

9.3. Immunohistochemistry Assay Development.

9.4. Sending a Study to a Contract Laboratory vs. Running In-house.

9.5. Choosing and Working with an Outside Laboratory— Keys for a Succe.ssful Relationship—What to Do before a Slide Is Stained.

9.6. Running and Managing Outsourced Clinical Studies

9.7. Applications of IHC in Drug Discovery and Development Process.

9.8. Conclusion.

References.

10 QUANTIFICATION OF MOLECULAR PATHOLOGY: COLORIMETRIC IMMUNOHISTOCHEMISTRY (Raphael Marcelpoil).

10.1. Introduction.

10.2. Imaging Devices and Systems.

10.3. Quantifi cation: Introduction to Colorimetric Image Analysis.

10.4. Measuring Colorimetric Information.

10.5. Chromogen Separation.

10.6. Measuring Information.

10.7. Conclusion.

References.

11 AQUA® TECHNOLOGY AND MOLECULAR PATHOLOGY (Mark Gustavson, Marisa Dolled-Filhart, Jason Christiansen, Robert Pinard, and David Rimm).

11.1. Introduction.

11.2. AQUA Technology—How It Works.

11.3. Standardization.

11.4. Quantification.

11.5. Localization.

11.6. Multiparametric Analysis.

11.7. Application of AQUA Technology to Drug Discovery and Companion Diagnostics.

11.8. Summary and Conclusions.

References.

Index.