Molecular Pathology in Drug Discovery and Development

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ISBN: 9780470145593 | 0470145595
Cover: Hardcover
Copyright: 8/17/2009

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The pharmaceutical industry is looking for new ways to better identify populations that will react positively to new drugs, and molecular pathology can fill that need. Molecular Pathology in Drug Discovery and Development provides an authoritative overview of molecular pathology and its applications and explains the significance of molecular pathology approaches to drug discovery and development. This book is an essential resource for practitioners in drug discovery and development, preclinical and clinical researchers, toxicologists and pharmacologists, molecular and cell biologists, and pathologists.

Preface	p. xv
Contributors	p. xvii
Molecular Pathology and Drug Development	p. 1
General Pathology	p. 1
General Aspects	p. 2
Molecular Pathology, the Molecular Way	p. 2
Loss of Gene Expression	p. 3
Translocations	p. 5
Detection of Pathogens	p. 5
Forensic Identification	p. 6
Protein Changes	p. 7
Other Methods of Detection	p. 8
Application of Molecular Pathology	p. 8
Molecular Pathology in Drug Development	p. 10
Most Important Molecular Pathologic Consideration	p. 11
Pharmaceutical Drug Development	p. 12
Introduction	p. 12
Drug Discovery and Development	p. 12
References	p. 18
Molecular Pathology in Oncology Target and Drug Discovery	p. 21
Introduction	p. 21
History of Chemotherapy and Cancer Drug Discovery	p. 22
Target-Based Drug Discovery	p. 26
Utilization of Molecular Pathology in the Discovery of Novel Cancer Targets	p. 29
Hit Identification and In Vitro Lead Optimization	p. 34
Implications for Molecular Pathology in Cancer Drug Development and Use	p. 39
Summary and Future Considerations	p. 41
References	p. 42
Molecular Pathology and Transcriptional Profiling in Early Drug Development	p. 47
Introduction	p. 47
Biomarkers in Clinical Setting and in Early Drug Development	p. 47
Advantages of Biomarker Implementation	p. 51
Changing Paradigm in Clinical Drug and Biomarker Development	p. 53
Promises of Transcriptional Profiling	p. 55
Biomarker Development and Validation Using Microarray Analysis	p. 59
Neoadjuvant Chemotherapy as an Intriguing Model for Biomarker Development	p. 62
Transcriptional Profiling for Identification of Individual Genes as Biomarkers	p. 64
Transcriptional Profiling for the Definition of Multigene Predictors Using Transcriptional Profiling	p. 66
Multigene Predictors of Chemotherapy Response	p. 69
Multigene Predictor of Response to a Targeted Therapy Agent	p. 71
Novel Approaches to Phase II Clinical Trial Design	p. 72
Novel Tools for Pathway Analysis	p. 74
Implementation of Biomarkers into the Clinical Setting	p. 75
Conclusion	p. 77
References	p. 77
Molecular Pathology in Nonclinical Safety Assessment	p. 85
Introduction	p. 85
Drug Development	p. 87
Immunohistochemistry in Drug Development	p. 89
Drug Discovery	p. 91
Target Validation and Target-Related Safety Concerns	p. 92
Off-Target Effects	p. 96
Biopharmaceuticals	p. 106
Summary	p. 109
References	p. 109
Toxicogenomics in Drug Development	p. 111
Introduction	p. 111
Brief Overview of Large-Scale Gene Expression Technologies	p. 113
RNA Quality	p. 113
Hybridization Platforms	p. 114
Analysis of Microarray Data	p. 117
Normalization and Filtering	p. 117
Analyzing for Differences between Experimental Samples	p. 118
Familywise Error Rate	p. 119
Resampling	p. 119
Expression Profile Analysis	p. 120
Pathway Analysis	p. 120
Gene Expression Databases	p. 121
Analyzing Relatedness of Gene Expression Profiles	p. 121
Application of Toxicogenomics in Drug Development	p. 127
Discovery	p. 127
Safety Testing	p. 128
Idiosyncratic Toxicity	p. 128
Considerations for Toxicogenomic Study Design	p. 129
In Vitro Studies	p. 129
In Vitro Studies	p. 131
Overview of Major Regulatory Developments Related to Use of Toxicogenomics in Drug Discovery and Development	p. 132
Data Submission	p. 132
Voluntary Genomic Data Submission	p. 133
Summary	p. 134
References	p. 135
Choosing and Working with an Outside Laboratory-Keys for a Successful Relationship-What to Do before a Slide Is Stained	p. 240
Finding the Right Laboratory, Asking the Right Questions	p. 240
What to Look for When Choosing/Evaluating a Laboratory to Outsource IHC Studies	p. 241
Relationship between Sponsor and Contract Laboratory	p. 243
Roles for a Successful Relationship	p. 244
Running and Managing Outsourced Clinical Studies	p. 247
Confidentiality Agreement	p. 247
Proposals and Contracts	p. 248
Project Initiation and Study Protocol	p. 248
IHC Assay Development/Finalize Assays for Study	p. 249
Sample Handling	p. 249
Testing of Study Samples	p. 249
Scoring of Study Samples	p. 249
Reporting and Documentation of Outsourced IHC Studies	p. 250
Quality Assurance Review of GLP Studies	p. 251
Data Submission	p. 252
Data Integration and Follow-up	p. 252
Applications of IHC in Drug Discovery and Development Process	p. 253
Target Validation	p. 253
Preclinical Testing	p. 253
Phase I through Phase III Clinical Studies	p. 255
Companion Diagnostics	p. 255
Conclusion	p. 257
References	p. 257
Quantification of Molecular Pathology: Colorimetric Immunohistochemistry	p. 259
Introduction	p. 260
Imaging Devices and Systems	p. 265
Quantification: Introduction to Colorimetric Image Analysis	p. 268
Image Acquisition	p. 269
Resolution and Magnification	p. 269
Sensor Size	p. 270
Two Major Camera Technologies Available for Color Image Acquisition	p. 271
Measuring Colorimetric Information	p. 272
The Lambert-Beer Law	p. 272
Koehler Illumination	p. 272
Additive Property of the Lambert-Beer Law	p. 274
Correction of Chromatic Aberration	p. 275
Chromogen Separation	p. 276
Looking at Each Pixel as a Set of Linear Equations	p. 276
Shading Correction	p. 278
Solution of Linear Algebraic Equations-Matrices	p. 280
Absorption Coefficient	p. 282
Example	p. 282
Generating Artificial Marker Images	p. 283
Measuring Information	p. 284
Image Segmentation	p. 285
Cell Scoring	p. 285
Multiplexing and Tissue Microarrays	p. 287
Conclusion	p. 293
References	p. 294
AQUA (R) Technology and Molecular Pathology	p. 295
Introduction	p. 295
AQUA Technology-How It Works	p. 298
Staining Methodology	p. 298
Tissue Microarray Technology	p. 301
Automated Fluorescence Microscopy and Image Acquisition	p. 301
Automated Image Validation	p. 302
AQUA (Image) Analysis-Producing an AQUA Score	p. 303
Standardization	p. 308
Quantification	p. 314
Localization	p. 321
Multiparametric Analysis	p. 322
Pathway Diagnostics	p. 325
Application of AQUA Technology to Drug Discovery and Companion Diagnostics	p. 325
Summary and Conclusions	p. 327
References	p. 328
Index	p. 335
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Molecular Pathology in Drug Discovery and Development

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