Molecular pathology in drug discovery and development:
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| Format: | Book |
| Language: | English |
| Published: |
Hoboken, NJ
Wiley
2009
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| Subjects: | |
| Online Access: | Umschlagbild Inhaltsverzeichnis |
| Item Description: | Literaturangaben |
| Physical Description: | XX, 349, [24] S. Ill., graph. Darst. 24 cm |
| ISBN: | 9780470145593 0470145595 |
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| adam_text | Titel: Molecular pathology in drug discovery and development
Autor: Platero, J. Suso
Jahr: 2009
CONTENTS
Preface xv
Contributors xvii
1 MOLECULAR PATHOLOGY AND DRUG DEVELOPMENT 1
Franz Fogt and J. Suso Platero
1.1. General Pathology 1
1.2. General Aspects 2
1.3. Molecular Pathology, the Molecular Way 2
1.3.1. Loss of Gene Expression 3
1.3.2. Translocations 5
1.3.3. Detection of Pathogens 5
1.3.4. Forensic Identification 6
1.3.5. Protein Changes 7
1.3.6. Other Methods of Detection 8
1.4. Application of Molecular Pathology 8
1.5. Molecular Pathology in Drug Development 10
1.5.1. Most Important Molecular Pathologic Consideration 11
1.6. Pharmaceutical Drug Development 12
1.6.1. Introduction 12
1.6.2. Drug Discovery and Development 12
References 18
2 MOLECULAR PATHOLOGY IN ONCOLOGY TARGET AND
DRUG DISCOVERY 21
Rolf-P. Ryseck, Ricardo Attar, Matthew V. Lorenzi,
and Brent A. Rupnow
2.1. Introduction 21
2.2. History of Chemotherapy and Cancer Drug Discovery 22
2.3. Target-Based Drug Discovery 26
2.4. Utilization of Molecular Pathology in the Discovery of
Novel Cancer Targets 29
vii
VJJi CONTENTS
2.5. Hit Identification and In Vitro Lead Optimization 34
2.6. Implications for Molecular Pathology in Cancer Drug
Development and Use 39
2.7. Summary and Future Considerations 41
References 42
3 MOLECULAR PATHOLOGY AND TRANSCRIPTIONAL PROFILING
IN EARLY DRUG DEVELOPMENT 47
Cornelia Liedtke, Lajos Pusztai, and W. Fraser Symmans
3.1. Introduction 47
3.2. Biomarkers in Clinical Setting and in Early Drug
Development 47
3.3. Advantages of Biomarker Implementation 51
3.4. Changing Paradigm in Clinical Drug and
Biomarker Development 53
3.5. Promises of Transcriptional Profiling 55
3.6. Biomarker Development and Validation Using
Microarray Analysis 59
3.7. Neoadjuvant Chemotherapy as an Intriguing Model for
Biomarker Development 62
3.8. Transcriptional Profiling for Identification of
Individual Genes as Biomarkers 64
3.9. Transcriptional Profiling for the Definition of Multigene
Predictors Using Transcriptional Profiling 66
3.9.1. Multigene Predictors of Chemotherapy Response 69
3.9.2. Multigene Predictor of Response to a Targeted
Therapy Agent 71
3.9.3. Novel Approaches to Phase II Clinical Trial Design 72
3.10. Novel Tools for Pathway Analysis 74
3.11. Implementation of Biomarkers into the Clinical Setting 75
3.12. Conclusion 77
References 77
4 MOLECULAR PATHOLOGY IN NONCLINICAL
SAFETY ASSESSMENT 85
Richard A. Westhouse
4.1. Introduction 85
4.2. Drug Development 87
4.2.1. Immunohistochemistry in Drug Development 89
CONTENTS iX
4.3. Drug Discovery 92
4.3.1. Target Validation and Target-Related Safety
Concerns 92
4.3.2. Off-Target Effects 96
4.4. Biopharraaceuticals 106
4.5. Summary 109
References 109
5 TOXICOGENOMICS IN DRUG DEVELOPMENT 111
Wayne R. Buck and Eric A. G. Blomme
5.1. Introduction 111
5.2. Brief Overview of Large-Scale Gene Expression
Technologies 113
5.2.1. RNA Quality 113
5.2.2. Hybridization Platforms 114
5.3. Analysis of Microarray Data 117
5.3.1. Normalization and Filtering 117
5.3.2. Analyzing for Differences between
Experimental Samples 118
5.3.3. Family wise Error Rate 119
5.3.4. Resampling U9
5.3.5. Expression Profile Analysis 120
5.3.6. Pathway Analysis 120
5.3.7. Gene Expression Databases 121
5.3.8. Analyzing Relatedness of Gene Expression Profiles 121
5.4. Application of Toxicogenomics in Drug Development 127
5.4.1. Discovery 127
5.4.2. Safety Testing 128
5.4.3. Idiosyncratic Toxicity 128
5.5. Considerations for Toxicogenomic Study Design 129
5.5.1. In Vitro Studies 129
5.5.2. In Vivo Studies 131
5.6. Overview of Major Regulatory Developments Related to
Use of Toxicogenomics in Drug Discovery and
Development 132
5.6.1. Data Submission 132
5.6.2. Voluntary Genomic Data Submission 133
5.7. Summary 134
References 135
x CONTENTS
6 MOLECULAR PATHOLOGY AS A WAY TO FIND
THE RIGHT DOSE FOR A DRUG 143
F. Rojo, A. Rovira, S. Serrano, and J. Albanell
6.1. Introduction 143
6.2. Anti-EGFR-Targeted Therapies:
The Pharmacodynamic Experience 145
6.3. Molecular Pathology with Small Molecules Gefitinib
and Erlotinib 148
6.4. Molecular Pathology with Cetuximab and Other
Monoclonal Antibodies to EGFR 152
6.5. Proteasome Inhibitors: Pharmacodynamics on
Blood Samples 155
6.6. Pharmacodynamics with Rapamycin Analogs 156
6.7. Second Generation of Targeted Therapies:
Multitarget Agents 159
6.8. Conclusions and Perspectives: Phase 0 Clinical Trials 163
References 164
7 MOLECULAR PATHOLOGY IN LIFE-CYCLE MANAGEMENT
IN DRUG DEVELOPMENT 169
Martha Quezado, Carlos A. Torres-Cabal, and David Berman
7.1. Introduction 169
7.2. Molecular Pathology Techniques 169
7.3. Practical Applications of Molecular Pathology Biomarkers 172
7.3.1. Selection of Methylating Chemotherapeutic
Regimen 172
7.3.2. Epidermal Growth Factor Receptor Expression
Is Important Biomarker in Many Tumors 175
7.3.3. Gastrointestinal Stromal Tumor and KIT Evaluation 180
7.3.4. Chronic Myeloid Leukemia and BCR-ABL
Protooncogene 182
7.4. Conclusion 184
References 185
8 MOLECULAR PATHOLOGY AND MOLECULAR THERAPY 195
Hewei Li
8.1. Introduction 195
8.2. Molecular Therapy Strategies 196
8.2.1. Mutation Compensation 196
CONTENTS XI
8.2.2. Gene Therapy in Drug Development 202
8.2.3. Immunogene Therapy 205
8.2.4. Oncolytic Viruses 206
8.2.5. Antiangiogenic Therapy 207
8.2.6. Engineered RNA Gene Therapy 208
8.3. Molecular Therapy Clinical Trials 209
References 211
9 MOLECULAR PATHOLOGY: IMMUNOHISTOCHEMISTRY
ASSAYS IN DRUG DEVELOPMENT PERFORMED BY
A CONTRACT RESEARCH LABORATORY 221
Frank Lynch and Steve Bernstein
9.1. Immunohistochemistry Is the Technique of Microscopic
Visualization of Target Protein* in Tissue Sections Using
Specific Antibodies 222
9.2. Basics of the IHC Assay 225
9.2.1. Formalin Fixation and Paraffin Embedding
of Tissues 226
9.2.2. Tissue Pretreatment/Antigen Unmasking 227
9.2.3. Blocking Step 227
9.2.4. Primary Antibody 228
9.2.5. Secondary Antibody 229
9.2.6. Hydrogen Peroxide Block 229
9.2.7. Avidin-Biotin Complex Peroxidase 229
9.2.8. Chromagen 230
9.2.9. Counterstain 230
9.2.10. Coverslip 230
9.3. Immunohistochemistry Assay Pevelopmetit 231
9.4. Sending a Study to a Contract Laboratory vs.
Running In-house 232
9.4.1. Turn-around Time 233
9.4.2. In-house Expertise 233
9.4.3. Throughput Capacity and Range of Services 235
9.4.4. Laboratory Infrastructure 236
9.4.5. Costs 237
9.4.6. Lab Certifications 238
9.4.7. Third-Party Testing 239
9.4.8. Future Considerations for Partnering 239
xii CONTENTS
9.5. Choosing and Working with an Outside Laboratory—
Keys for a Successful Relationship—What to Do before
a Slide Is Stained 240
9.5.1. Finding the Right Laboratory, Asking the
Right Questions 240
9.5.2. What to Look for When Choosing/Evaluating
a Laboratory to Outsource IHC Studies 241
9.5.3. Relationship between Sponsor and Contract
Laboratory 243
9.5.4. Roles for a Successful Relationship 244
9.6. Running and Managing Outsourced Clinical Studies 247
9.6.1. Confidentiality Agreement 247
9.6.2. Proposals and Contracts 248
9.6.3. Project Initiation and Study Protocol 248
9.6.4. IHC Assay Development/Finalize Assays for Study 249
9.6.5. Sample Handling 249
9.6.6. Testing of Study Samples 249
9.6.7. Scoring of Study Samples 249
9.6.8. Reporting and Documentation of Outsourced
IHC Studies 250
9.6.9. Quality Assurance Review of GLP Studies 251
9.6.10. Data Submission 252
9.6.11. Data Integration and Follow-up 252
9.7. Applications of IHC in Drug Discovery and
Development Process 253
9.7.1. Target Validation 253
9.7.2. Preclinical Testing 253
9.7.3. Phase I through Phase III Clinical Studies 255
9.7.4. Companion Diagnostics 255
9.8. Conclusion 257
References 257
10 QUANTIFICATION OF MOLECULAR PATHOLOGY:
COLORIMETRICIMMUNOHISTOCHEMISTRY 259
Raphael Marcelpoil
10.1. Introduction 260
10.2. Imaging Devices and Systems 265
10.3. Quantification: Introduction to Colorimetric Image Analysis 268
10.3.1. Image Acquisition 269
10.3.2. Resolution and Magnification 269
CONTENTS Xiii
10.3.3. Sensor Size 270
10.3.4. Two Major Camera Technologies Available for
Color Image Acquisition 271
10.4. Measuring Colorimetric Information 272
10.4.1. The Lambert-Beer Law 272
10.4.2. Koehler Illumination 272
10.4.3. Additive Property of the Lambert-Beer Law 274
10.4.4. Correction of Chromatic Aberration 275
10.5. Chromogen Separation 276
10.5.1. Looking at Each Pixel as a Set of Linear Equations 276
10.5.2. Shading Correction 278
10.5.3. Solution of Linear Algebraic Equations-—Matrices 280
10.5.4. Absorption Coefficient 282
10.5.5. Example 282
10.5.6. Generating Artificial Marker Images 283
10.6. Measuring Information 284
10.6.1. Image Segmentation 285
10.6.2. Cell Scoring 285
10.6.3. Multiplexing and Tissue Microarrays 287
10.7. Conclusion 293
References 294
11 AQUA® TECHNOLOGY AND MOLECULAR PATHOLOGY 295
Mark Gustavson, Marisa Dolled-Filhart, Jason Christiansen,
Robert Pinard, and David Rimm
11.1. Introduction 295
11.2. AQUA Technology—How It Works 298
11.2.1. Staining Methodology 298
11.2.2. Tissue Microarray Technology 301
11.2.3. Automated Fluorescence Microscopy and Image
Acquisition 301
11.2.4. Automated Image Validation 302
11.2.5. AQUA (Image) Analysis—Producing an
AQUA Score 303
11.3. Standardization 308
11.4. Quantification 314
11.5. Localization 321
11.6. Multiparametric Analysis 322
11.6.1. Pathway Diagnostics 325
Xiv CONTENTS
11.7. Application of AQUA Technology to Drug Discovery and
Companion Diagnostics 325
11.8. Summary and Conclusions 327
References 328
Index 335
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| spelling | Molecular pathology in drug discovery and development ed. by J. Suso Platero Hoboken, NJ Wiley 2009 XX, 349, [24] S. Ill., graph. Darst. 24 cm txt rdacontent n rdamedia nc rdacarrier Literaturangaben Molekularpathologie (DE-588)4170396-0 gnd rswk-swf Arzneimittelentwicklung (DE-588)4143176-5 gnd rswk-swf Drug development. Pathology, Molecular. Molekularpathologie (DE-588)4170396-0 s Arzneimittelentwicklung (DE-588)4143176-5 s DE-604 Platero, J. Suso edt http://media.obvsg.at/AC07994478-4001 UBG Umschlagbild HBZ Datenaustausch application/pdf http://bvbr.bib-bvb.de:8991/F?func=service&doc_library=BVB01&local_base=BVB01&doc_number=020420151&sequence=000002&line_number=0001&func_code=DB_RECORDS&service_type=MEDIA Inhaltsverzeichnis |
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| subject_GND | (DE-588)4170396-0 (DE-588)4143176-5 |
| title | Molecular pathology in drug discovery and development |
| title_auth | Molecular pathology in drug discovery and development |
| title_exact_search | Molecular pathology in drug discovery and development |
| title_full | Molecular pathology in drug discovery and development ed. by J. Suso Platero |
| title_fullStr | Molecular pathology in drug discovery and development ed. by J. Suso Platero |
| title_full_unstemmed | Molecular pathology in drug discovery and development ed. by J. Suso Platero |
| title_short | Molecular pathology in drug discovery and development |
| title_sort | molecular pathology in drug discovery and development |
| topic | Molekularpathologie (DE-588)4170396-0 gnd Arzneimittelentwicklung (DE-588)4143176-5 gnd |
| topic_facet | Molekularpathologie Arzneimittelentwicklung |
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