Pharmacogenomics in Drug Discovery and Development

719 Pages·2014·9.657 MB·English

by  Qing Yan (eds.)

Methods in
Molecular Biology 1175
Qing Yan Editor
Pharmacogenomics
in Drug Discovery
and Development
Second Edition
M M B
ETHODS IN OLECULAR IOLOGY
Series Editor
John M. Walker
School of Life Sciences
University of Hertfordshire
Hat fi eld, Hertfordshire, AL10 9AB, UK
For further volumes:
http://www.springer.com/series/7651

Pharmacogenomics in Drug
Discovery and Development
Second Edition
Edited by
Qing Yan
PharmTao, Santa Clara, CA, USA
Editor
Qing Y an
PharmTao
Santa Clara, CA, USA
ISSN 1064-3745 ISSN 1940-6029 (electronic)
ISBN 978-1-4939-0955-1 ISBN 978-1-4939-0956-8 (eBook)
DOI 10.1007/978-1-4939-0956-8
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Prefa ce
Pharmacogenomics is considered the future of drug therapy. It is a rapidly growing area in
the recognition of the necessity of personalized medicine, a medicine that deals with the
complexity of the human body. Because of the diversity of patients’ biological backgrounds,
the same disease may be caused by genetic variations in different people, who will respond
differently to the same drug. Such situations require individualized treatment that avoids
adverse drug responses and ensures the best possible results. The development of pharma-
cogenomics represents the evolution of biomedicine from treating the disease itself to treating
the malfunction of an individual person, the “root” of diseases. With the change of focus
from disease-centered to human-centric medicine, pharmacogenomics brings hope for the
transformation from simple disease treatment to accurate prediction and effective prevention.
For the drug discovery and development industry, pharmacogenomics is useful in identifying
drug targets to obtain the optimal drug effi cacy for specifi c patient groups.
However, many challenges need to be resolved before pharmacogenomics can be
applied in the clinic. Most importantly, the mechanisms inside the human bodies that control
therapeutic responses are complex and multifactorial. It is necessary to elucidate the
complexity in various spatial and temporal levels, such as the interactions among genes,
drugs, as well as natural and psychosocial environments at various physiological and patho-
logical stages. Accurate biomarkers and effective drug targets can be found only based on
such understanding at system levels.
In this book, we approach these challenges from several angles. In the fi rst part of the
book, we introduce some novel concepts and important cutting-edge technologies that are
useful for the development of system-based pharmacogenomics to solve the complexity
(s ee Part I). A framework of systems and dynamical medicine is proposed on the basis of the
understanding of the properties of complex adaptive systems (CASs) ( see Chapter 1 ).
Various “omics” technologies such as approaches in bioinformatics and transcriptomics are
described to support the system analyses ( see Chapters 2 and 3 ). These methods are useful
for understanding the complex and dynamical interconnections and interactions among
genes, drugs, diseases, and the environment. Network and dynamical models can be estab-
lished for the identifi cation of robust biomarkers to evaluate disease states, disease progression,
and therapeutic responses ( see Chapter 1 ) .
For example, bioinformatics is essential in fi nding the spatiotemporal patterns in phar-
macogenomics, including the time-series analyses for the elucidation of structure–function
associations at various disease stages. Specifi c experimental methods are also introduced,
such as the mutational analysis procedures on paraffi n-embedded tumors for the prediction
of individual responses to anticancer therapy (s ee Chapter 4 ). The combination of bioinfor-
matics and experimental approaches is helpful for studying drug adverse effects such as
those caused by statin, including genotyping, phenotyping, and statistical analysis strategies
(s ee Chapter 5 ) .
Another feature of this volume is the emphasis on the examinations of gene–drug
interactions, that is, how drugs act and how they are processed in the human body, includ-
ing drug absorption, distribution, metabolism, and excretion. Biomarkers and molecules
v
vi Preface
such as ion channels, membrane transporters, receptors, and enzymes are playing increasingly
essential roles in drug design and pharmacogenomics studies ( see Chapters 6 , 7 , 8 , and 9 ).
These biomarkers provide critical links between drug discovery and diagnostics efforts.
Updated introductions and detailed methods about studies in these molecules are provided
in this book. For example, membrane transporters are profoundly involved in drug disposition
through transporting substrate drugs between organs and tissues. Investigations of genetic
variations, genotyping methods, and substrate identifi cation of membrane transporters are
helpful for drug design and development (s ee Chapter 6 ). Methods for the clinical develop-
ment of transporter markers can be meaningful for the practice of translational medicine.
In addition, studies of G protein-coupled receptors (GPCRs) may provide insight into
disease pathways, such as the involvement of the regulator of G protein signaling (RGS) pro-
tein polymorphisms in hypertension. Pharmacogenomics of GPCR studies the involvement
of genetic variations in structural and functional roles, such as GPCR activation and inactiva-
tion, their relationships with diseases, and their potential uses in defi ning optimized novel
drug targets (s ee Chapters 7 , 8 , and 9 ) . These investigations can be useful for refi ning drug
discovery because GPCR disorders are associated with a wide variety of human diseases,
including obesity, diabetes, cardiovascular diseases, cancer, asthma, and infectious diseases.
The second part of this book focuses on how to translate pharmacogenomics studies
from the “bench side” to the “bedside” in clinical therapies of diseases to support the devel-
opment of translational medicine ( see Part II). These diseases include cardiovascular dis-
eases, cancer, Alzheimer’s disease, psychiatric disorders, rheumatoid arthritis, osteoporosis,
and pediatric diseases. Comprehensive information for each disease system is discussed,
including biomarkers involved in the diseases and the associations among genes, diseases,
drug responses, and the environment. For example, genetic variations may play important
roles in heart failure pharmacotherapy (s ee Chapter 1 0 ) . Pharmacogenomics studies are
making signifi cant contributions toward the elucidation of pharmacological atheroprotec-
tion for fi nding novel therapeutic approaches for atherosclerosis, the condition that can
result in stroke, myocardial infarction, and death (s ee Chapter 1 1 ) . In cancer therapy, trans-
lational investigations in pharmacogenomics may also make genetic profi ling effective for
the analysis of chemotherapy-induced neurotoxicity (CIPN) (Chapter 12 ) .
As a complex disorder with multifactorial clinical features, Alzheimer’s disease (AD)
needs to be studied in the context of diverse environmental impacts, cerebrovascular
dysfunction, epigenetic phenomena, as well as various structural and functional genomic
dysfunctions ( see Chapter 1 3 ) . This book provides a comprehensive and detailed discussion
of the pharmacogenomics of AD, from functional genomics to therapeutic strategies, from
the discovery of reliable biomarkers to the optimized drug development.
The identifi cation of pharmacogenomic biomarkers for the prediction of drug effi cacy
and adverse reactions is a growing area of research in the studies of psychiatric disorders
such as schizophrenia (s ee Chapter 1 4 ). Such methods have the potential to replace the
current trial-and-error approach for the optimal treatment selections toward the personal-
ized medicine. Pharmacogenomics investigations may also elucidate the roles of genetic,
biological, social, and environmental components in the therapeutic responses of drug
addiction (s ee Chapter 1 5 ) .
For rheumatoid arthritis (RA), the pharmacogenomics of traditional disease-modifying
antirheumatic drugs (DMARDs) as well as the newer biologic DMARDs are discussed in
details for individualized therapy ( see Chapter 1 6 ) . In addition, with comprehensive exami-
nations including genome-wide association studies, exciting opportunities are open to provide
a better insight into the pharmacogenomics of osteoporosis and osteoporotic fractures
Preface vii
(s ee Chapter 1 7 ). In pediatrics, developmental changes may account for the variability in
drug responses. Various “omics” approaches including genome-wide haplotype mapping,
proteomics, epigenomics, as well as genetic epidemiological studies over years may expand
the scope of personalized therapies in children ( see Chapters 1 8 and 1 9 ).
By covering topics from individual molecules to systemic diseases, from basic concepts
to advanced technologies, this book intends to provide a practical, state-of-the-art, and
integrative view of the application of pharmacogenomics in drug discovery and develop-
ment. A wide range of theoretical and experimental approaches are introduced to meet the
problem-solving objectives for understanding the complexity in health and diseases, from
laboratory tests to computational analysis. Written by leading experts in the fi eld, this book
intends to provide comprehensive resources and a holistic view for the translation of phar-
macogenomics into better preventive and personalized medical care.
I would like to thank all of the authors for their valuable contributions to this exciting
fi eld. I also thank the series editor, Dr. John Walker, for his help with the editing.
Santa Clara, CA, USA Qing Yan, M.D., Ph.D.

Contents
Preface. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . v
Contributors. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . x i
PART I SYSTEMS AND “OMICS” STUDIES IN PHARMACOGENOMICS
1 From Pharmacogenomics and Systems Biology to Personalized Care:
A Framework of Systems and Dynamical Medicine . . . . . . . . . . . . . . . . . . . . . 3
Qing Yan
2 T ranslational Bioinformatics Approaches for Systems
and Dynamical Medicine. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19
Qing Yan
3 W hole Blood Transcriptomic Analysis to Identify Clinical Biomarkers
of Drug Response. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 35
Grant P . Parnell and David R. Booth
4 D iagnostic Procedures for Paraffin-Embedded Tissues Analysis
in Pharmacogenomic Studies. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 45
Raffaele P almirotta, M aria Laura D e Marchis, Giorgia Ludovici,
Patrizia Ferroni, P asquale A bete, F iorella Guadagni,
and David D ella-Morte
5 A pproach to Clinical and Genetic Characterization
of Statin-Induced Myopathy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6 7
QiPing Feng
6 P harmacogenetics of Membrane Transporters: A Review
of Current Approaches . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9 1
Tristan M. S issung, A ndrew K. L . G oey, A riel M. Ley,
Jonathan D. Strope, and William D. F igg
7 G Protein-Coupled Receptor Accessory Proteins and Signaling:
Pharmacogenomic Insights. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 121
Miles D. Thompson, D avid E . C. C ole, Pedro A. Jose, and P eter C hidiac
8 G Protein-Coupled Receptor Mutations and Human Genetic Disease. . . . . . . 1 53
Miles D. Thompson, G eoffrey N . H endy, Maire E. P ercy,
Daniel G. B ichet, and David E.C . C ole
9 P harmacogenetics of the G Protein-Coupled Receptors. . . . . . . . . . . . . . . . . . 1 89
Miles D . T hompson, D avid E .C. Cole, V alerie Capra,
Katherine A. Siminovitch , G . Enrico Rovati , W . McIntyre Burnham ,
and Brinda K . R ana
PART II CLINICAL APPLICATIONS OF PHARMACOGENOMICS
10 Pharmacogenomics of Heart Failure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2 45
Anastasios L ymperopoulos and Faren F rench
ix