Novel Anticancer Agents: Strategies for Discovery and Clinical Testing

478 Pages·2005·26.99 MB·English

by  Alex A. Adjei

Novel Anticancer Agents
Strategies for Discovery
and Clinical Testing
This Page Intentionally Left Blank
Novel Anticancer Agents
Strategies for Discovery
and Clinical Testing
Editors
Alex A. Adjei
Mayo Clinic and Foundation
Rochester, Minnesota
John K. Buolamwini
College of Pharmacy
University of Tennessee Health Science Center
Memphis, Tennessee
AMSTERDAM " BOSTON " HEIDELBERG (cid:12)9 LONDON
NEW YORK (cid:12)9 OXFORD (cid:12)9 PARIS " SAN DIEGO
SAN FRANCISCO " SINGAPORE (cid:12)9 SYDNEY (cid:12)9 TOKYO
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CONTENTS
CONTRIBUTORS XI
PREFACE XV
I l l
STRATEGIES FOR DRUG DISCOVERY
A Survey of Novel Molecular Targets for
Anticancer Drug Discovery
JOHN K. BUOLAMWlNI
I. Introduction 1
II. Overview of Growth Factor Induced Mitogenic Signaling
III. Protein Kinases and Phosphatases 4
IV. Adapter Proteins 12
V. GTP-Binding Proteins 12
VI. Oncogenic Transcription Factors 13
VII. Apoptosis, Cell Survival, and Life Span Targets 15
VIII. Angiogenesis and Metastasis Molecular Factors 17
IX. Protein Degradation and Chaperoning Targets 19
X. Chromatin Remodeling Factors 19
XI. Conclusion 20
References 20
V
VI CONTENTS
2 Microarrays: Small Spots Produce Major Advances
Pharmacogenomics
in
M. NEESW, . KUSNEZOWA, ND C. D. WOODWORTH
I. Introduction to Microarrays 38
II. Advantages of DNA Microarrays 44
III. Major DNA Array Formats: Something for Everyone 45
IV. What is the Best Way to Interface with Microarrays? 52
V. Microarrays and Pharmacogenomics: Revolutionizing Discovery of New
Drugs and Gene Function 55
VI. What Can Go Wrong in cDNA Microarray Experimentation? 65
VII. Array-Based Proteomics: How to Investigate Protein Complexity 68
VIII. Emerging Microarray Technologies for High-Throughput Proteome
Investigation: A Technical Overview 68
IX. Current and Future Applications of Protein Arrays in Drug Discovery 71
X. How to Deal with all that Data 73
XI. The Future is Only Going to Get Better 74
References 76
3 Strategies to Target Chemotherapeutics to Tumors
CHARLES E ALBRIGHT AND PEARL S. HUANG
I. Background and Rationale 83
II. Antibody-Directed Enzyme Prodrug Technique 84
III. Passive Tumor Targeting 84
IV. Targeting by Binding to Tumor Cell Surface Molecules 85
V. Enzyme-Activated Targeting 85
VI. Summary and Future Directions 90
References 90
4 QSAR and Pharmacophore Mapping Strategies
in Novel Anticancer Drug Discovery
JAMES J. KAMINSKI
I. Introduction 93
II. Pharmacophore Definition 94
III. Pharmacophore Validation 99
IV. Conclusions 104
References 104
5 Applications of Nuclear Magnetic Resonance and Mass
Spectrometry to Anticancer Drug Discovery
ROBERTP OWERSA ND MARSHALLM . SIEGEL
I. Introduction 107
II. NMR in Anticancer Drug Discovery 109
III. Mass Spectrometry in Anticancer Drug Discovery 140
CONTENTS VII
IV. MS/NMR Screening Assay 162
V. Conclusions 172
Acknowledgements 172
References 173
6 Antisense Strategies for the Development
of Novel Cancer Therapeutics
RUIWEN ZHANG AND HUI WANG
I. Introduction 191
II. Design and Evaluation of Antisence Oligonucleotides 193
III. Conclusion 202
Acknowledgements 203
References 203
7 Antibodies and Vaccines as Novel Cancer Therapeutics
SVETOMIR N. MARKOVIC AND ESTEBAN CELLS
I. Introduction 207
II. Anti-Tumor Antibodies 207
III. Cancer Vaccines 212
IV. Conclusion 218
References 219
8 Inhibitors of Apoptosis as Targets for Cancer Therapy
M. SAEED SHEIKH AND YING HUANG
I. The Inhibitors of Apoptosis 223
II. Concluding Remarks 229
References 230
9 Preclinical Testing and Validation
of Novel Anticancer Agents
LLOYD R. KELLAND
I. Introduction 233
II. Target Validation 234
III. A Generic Cascade for Anticancer Drug Discovery 235
IV. High-Throughput Cell-Free Screens for Activity Against the Target 237
V. In Vitro Cell Line Models 238
VI. In Vivo Testing of Novel Compounds 240
VII. Cassette-Dosing 240
VIII. Pharmaceutical Considerations 241
IX. High-Throughput In Vivo Anti-Tumor Testing: The Hollow Fiber
Assay 241
X. Human Tumor Xenografts 242
XI. Orthotopic, Transgenic, and Other Animal Models 243
VIII CONTENTS
XII. Pharmacodynamics 244
XIII. Summary 245
Acknowledgements 245
References 245
METHODS FOR CLINICAL TESTING OF NOVEL AGENTS
I0 Surrogate End Points and Biomarkers for Early Trials
of Novel Anticancer Agents
ALEX A. ADJEI
I. Introduction 249
II. What are Targeted Agents? 250
III. Surrogate Markers or Biomarkers? 250
IV. Biomarkers as Indicators of Drug Effect In Vivo 252
V. Biomarkers as Predictive Factors 252
VI. Biomarkers as Prognostic Factors 253
VII. Technical Issues in the Evaluation of Drug Effects In Vivo 254
VIII. Lessons for the Future 261
Acknowledgements 261
References 261
II Regulatory Considerations in Clinical Trials
of Novel Anticancer Drugs
GRANT WILLIAMS AND RICHARD PAZDUR
I. Introduction 263
II. Overview of Cancer Drug Regulation 264
III. Regulatory Considerations in Early Cancer Drug Development 267
IV. Regulatory Considerations in Late Drug Development 271
V. Conclusion 283
Acknowledgements 283
References 283
12 Improving the Efficacy and Safety of Anticancer
Agents--The Role of Pharmacogenetics
MARGARET-MARY AMEYAW AND HOWARD L. MCLEOD
I. Introduction 286
II. Thiopurine Methyltransferase 286
III. DPD 288
IV. Thymidylate Synthase 289
V. ABC Family of Drug Transporters 291
CONTENTS IX
VI. UDP-Glucuronosyltransferase IAI Pharmacogenetics and Irinotecan 292
VII. MTHFR Reductase Pharmacogenetics 293
VIII. Cytochrome P4503A Pharmacogenetics 293
IX. Conclusion 293
Acknowledgements 294
References 294
13 Imaging of Pharmacodynamic End Points
in Clinical Trials
ERIC O. ABOAGYE, A. R. PADHANI, AND PATRICIA M. PRICE
I. Introduction 300
II. PET 300
III. Evaluation of Cancer Therapeutics with PET 302
IV. MRI Assessment of Microvessel Function 311
V. Conclusions 328
References 328
14 Devising Proof-of-Concept Strategies
in Oncology Clinical Trials
PAUL S. WISSEL
I. Introduction 337
II. Proof-of-Concept 338
III. Elements of "The Concept" 339
IV. Application of Surrogate End Points in Proof-of-Concept Decision
Making 343
V. Selected Statistical Considerations in Proof-of-Concept Studies 349
VI. Pharmacodynamic Proof-of-Concept End Points 352
VII. Pharmacokinetic Proof-of-Concept End Points 356
VIII. Proceeding From Proof-of-Concept Directly to Phase III 359
IX. Guidelines and Summary 360
Acknowledgements 361
References 361
1 5 Clinical Trial Designs for Cytostatic Agents and Agents
Directed at Novel Molecular Targets
EDWARD L. KORN, LARRYV . RUBINSTEIN, SALLY A. HUNSBERGER, ]AMES M. PLUDA,
ELIZABETH EISENHAUER,A ND SUSAN G. ARBUCK
I. Introduction 366
II. Phase I Dose-Finding Trials 366
III. Preliminary Efficacy Trials 372
IV. Definitive Randomized Efficacy Trials 376
V. Conclusions 377
References 377