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Current
Pharmacogenomics & Personalized Medicine
ISSN: 1875-6913 (Online)
ISSN: 1875-6921 (Print)
Current Pharmacogenomics
& Personalized Medicine
Volume 7, Number 4, December 2009
Contents
Editorial:
Personalized Medicine Beyond Genomics: New Technologies,
Global Health Diplomacy and Anticipatory Governance Pp.
225-230
V. Ozdemir, D. Husereau, S. Hyland, S. Samper and
M.Z. Salleh
Feature Article
Small is Beautiful: What Can Nanotechnology Do for Personalized
Medicine? Pp. 231-237
G.E. Marchant
[Abstract] [Full
text article]
Defining Statistical Race and Phenotypic Race and
Their Implications for Health Disparities Pp. 238-242
S. S-J. Lee
[Abstract] [Full
text article]
Interview Article
Interview with Dr. Young-Ki Paik, President of the Human Proteome
Organization (HUPO): Pharmacoproteomics and the Approaching
Wave of “Proteomics Diagnostics” Pp.
243-248
Y.K. Paik, J.E. Graham, M. Jones, F. McDonald,
C. Holmes and V. Ozdemir
[Abstract] [Full
text article]
Expert Reviews
Human Genetic Variation, Population Pharmacokinetic –
Dynamic Models, Bayesian Feedback Control, and Maximally Precise
Individualized Drug Dosage Regimens Pp. 249-262
R. Jelliffe, A. Schumitzky, D. Bayard, R. Leary,
A. Botnen, M. Van Guilder, A. Bustad and M. Neely
[Abstract] [Full
text article]
Personalizing HER2-Targeted Therapy in Metastatic
Breast Cancer Beyond HER2 Status: What We Have Learned from
Clinical Specimens Pp. 263-274
R. Nahta, S. Shabaya, T. Ozbay and D.
L. Rowe
[Abstract] [Full
Text Article]
Dihydropyrimidine Dehydrogenase Genotyping and
Phenotyping for 5-Fluorouracil Dysmetabolism: Moving Towards
Personalized Chemotherapy in Patients with Cancer
Pp. 275-283
M. Eidens, S. Prause, A. Weise, M. Klemm, M.M. Weber and
A. Pfützner
[Abstract] [Full
text article]
Economic and Cost-Effectiveness Considerations
for Pharmacogenetics Tests: An Integral Part of Translational
Research and Innovation Uptake in Personalized Medicine Pp.
284-296
D. Paci and D. Ibarreta
[Abstract] [Full
text article]
Pharmacogenomics and Regional Capacity Building
Personalized and Predictive Medicine in Turkey: A Symposium
Report of the Istanbul Working Group on Personalized Medicine,
Istanbul, Turkey, September 10-12, 2009 Pp.
297-301
C. Hizel, S. Gök, S. Sardas, D. Bernard-Gallon, C. Maugard
and E. Genç, on behalf of the Istanbul Working
Group on Personalized Medicine
[Abstract] [Full
text article]
Letter to the Editor
Workshop
at WorldPharma2010, Copenhagen, Denmark: “Implementation
and Obstacles of Pharmacogenetics in Clinical Practice”,
July 20, 2010 Pp. 302
I. Cascorbi, on behalf of the IUPHAR Clinical Division Sub-Committee
on Pharmacogenetics
Erratum
Pp. 303
REVIEWER ACKNOWLEDGEMENT
Abstracts
[Back to top] [Full
text article]
Small is Beautiful: What Can Nanotechnology Do for
Personalized Medicine?
G.E. Marchant
Nanotechnology and personalized medicine are two of the most
rapidly emerging areas of biomedical research, as well as
two of the most promising technologies for improving health
care and health outcomes. They are also rapidly converging
in numerous current and future clinical applications. Examples
include the use of nanotechnology for improved DNA sequencing
and SNP analysis, the development of nano-therapeutics that
can target specific cell and tissue types, biosensors for
specific proteins and other molecules in vivo, and
point-of-care molecular diagnostic devices enabled by nanotechnology.
Nanotechnology offers many advantages for personalized medicine
applications, including a size that matches the scale of the
molecular substrates of personalized medicine, an increased
sensitivity in detecting and binding with target molecules,
and flexibility in the design and function of therapeutics
and diagnostics at the nano scale. Yet, at the same time,
the utilization of nanotechnology in personalized medicine
may create uncertainties or risk relating to potential toxicity.
In addition to describing the scientific and technical opportunities
and challenges in applying nanotechnology to personalized
medicine, this article also addresses some of the policy,
legal and ethical issues raised by the convergence of nanotechnology
and personalized medicine.
[Back to top] [Full
text article]
Defining Statistical Race and Phenotypic Race and
Their Implications for Health Disparities
S. S-J. Lee
Since the completion of the Human Genome Project, increasing
scrutiny has focused on patterns of genetic variation among
global populations and their association with disease and
human traits. This paper addresses emerging techniques to
identify genetic differences, including admixture mapping
and the use of ancestry informative markers (AIMS), towards
controlling population substructure in genetic association
studies. The paper discusses the need to reconcile statistical
race used to determine genetic ancestry with phenotypic
race in identifying and addressing ongoing health disparities
among human populations. As DNA biobanking grows and standards
for collecting phenotypic information are developed, clear
understanding of the varied approaches to defining race and
their implications will be imperative. Central to this explication
will be an exploration of how genetic technologies inform
current approaches to ancestry and their relevance for pharmacogenomic
applications.
[Back to top] [Full
text article]
Interview with Dr. Young-Ki Paik, President of the
Human Proteome Organization (HUPO): Pharmacoproteomics and
the Approaching Wave of “Proteomics Diagnostics”
Y.K. Paik, J.E. Graham, M. Jones, F. McDonald,
C. Holmes and V. Ozdemir
Dr. Young-Ki Paik directs the Yonsei Proteome Research Center
in Seoul, Korea and was elected as the President of the Human
Proteome Organization (HUPO) in 2009. In the December 2009
issue of the Current Pharmacogenomics and Personalized Medicine
(CPPM), Dr. Paik explains the new field of pharmacoproteomics
and the approaching wave of “proteomics diagnostics”
in relation to personalized medicine, HUPO’s role in
advancing proteomics technology applications, the HUPO Proteomics
Standards Initiative, and the future impact of proteomics
on medicine, science, and society. Additionally, he comments
that (1) there is a need for launching a Gene-Centric Human
Proteome Project (GC-HPP) through which all representative
proteins encoded by the genes can be identified and quantified
in a specific cell and tissue and, (2) that the innovation
frameworks within the diagnostics industry hitherto borrowed
from the genetics age may require reevaluation in the case
of proteomics, in order to facilitate the uptake of pharmacoproteomics
innovations. He stresses the importance of biological/clinical
plausibility driving the evolution of biotechnologies such
as proteomics, instead of an isolated singular focus on the
technology per se. Dr. Paik earned his Ph.D. in biochemistry
from the University of Missouri-Columbia and carried out postdoctoral
work at the Gladstone Foundation Laboratories of Cardiovascular
Disease, University of California at San Francisco. In 2005,
his research team at Yonsei University first identified and
characterized the chemical structure of C. elegans
dauer pheromone (daumone) which controls the aging process
of this nematode. He is interviewed by a multidisciplinary
team specializing in knowledge translation, technology regulation,
health systems governance, and innovation analysis.
[Back to top] [Full
text article]
Human Genetic Variation, Population Pharmacokinetic
– Dynamic Models, Bayesian Feedback Control, and Maximally
Precise Individualized Drug Dosage Regimens
R. Jelliffe, A. Schumitzky, D. Bayard, R. Leary,
A. Botnen, M. Van Guilder, A. Bustad and M. Neely
Variation in the behavior of drugs between people, and variation
in drug behavior in a given patient over time, have both presented
us with challenging problems in optimal description of such
behavior as well as challenges of how best to act on such
information. New high-throughput genotyping methods and measurement
of variations in gene expression over time present us with
issues of 1) how best to use such information in the overall
process of planning drug dosage regimens for individual patients,
especially if the drug is potentially toxic; 2) how to further
refine our knowledge about the patient during the course of
pharmacotherapy; and 3) how best to adjust the dosage regimen
to the new information we obtain about him/her as a unique
individual. Human genetic variation, in the form of gene sequence
or expression variability, provides us with important covariate
information to help further individualize our dosage regimen
for a particular patient based on that information, just as
does information about smoking status, age, gender, body weight,
and renal function, for example. It helps us consider the
patient as an individual rather than as a member of a larger
group. Variation in gene expression over time (i.e., transcriptomic
biomarkers) in an individual patient presents another problem,
as it can cause significant differences in drug behavior over
time. However, just as variation over time can occur in other
covariates such as body weight and renal function, so can
such changes in genetic expression over time be incorporated
into models of drug behavior in individual patients, and used
thoughtfully to optimize each patient’s drug dosage
regimen. The overall structure of optimally precise Bayesian
adaptive control is presented in this paper, to define explicitly
the context in which human genetic/genomic information can
be incorporated and used to optimize drug therapy for patients.
[Back to top] [Full
Text Article]
Personalizing HER2-Targeted Therapy in Metastatic
Breast Cancer Beyond HER2 Status: What We Have Learned from
Clinical Specimens
R. Nahta, S. Shabaya, T. Ozbay and
D. L. Rowe
HER2 is over-expressed in approximately 25% to 30% of
human metastatic breast cancers, primarily due to gene amplification.
There are currently two HER2-targeted therapies approved for
clinical use, the monoclonal HER2 antibody trastuzumab and
the EGFR/HER2 dual tyrosine kinase inhibitor lapatinib. Although
both agents show clinical benefit in a subset of patients
with metastatic breast cancer, many patients with HER2-over-expressing
metastatic breast tumors do not respond to these agents. Furthermore,
those who do show an initial response generally demonstrate
disease progression, on average in less than one year. It
has become clear that HER2 expression status alone does not
adequately predict response to HER2-targeted therapy. Identification
and clinical validation of molecular predictors of response
to trastuzumab and lapatinib is critical for further personalizing
treatment and improving clinical benefit for patients whose
tumors over-express HER2. In this review, we discuss published
data describing potential predictors of response or resistance
to trastuzumab and lapatinib. While a discussion of the preclinical
work is provided, the emphasis is placed on potential predictors
that have been studied in clinical specimens such as tumor
tissue or serum obtained from patients treated with HER2-targeted
therapy. The present analysis and synthesis of the available
literature therefore contribute towards an emerging knowledgebase
to personalize breast cancer treatment taking into factors
including but beyond HER2 expression.
[Back to top] [Full
text article]
Dihydropyrimidine Dehydrogenase Genotyping and Phenotyping
for 5-Fluorouracil Dysmetabolism: Moving Towards Personalized
Chemotherapy in Patients with Cancer
M. Eidens, S. Prause, A. Weise, M. Klemm, M.M. Weber and
A. Pfützner
Whether theranostic testing to discern person-to-person and
population differences in drug metabolism pathways offers
clinical guidance in oncology for fluoropyrimidines such as
5-fluorouracil (5-FU) remains an open question. Extensive
basic and clinical studies have been performed over the past
several decades with regard to personalizing treatment with
fluoropyrimidines, optimizing patients’ quality of life
and reducing risks for severe and fatal toxic events. A variety
of genetic variants in the dihydropyrimidine dehydrogenase
(DPYD) gene were thus identified, and have been clustered
according to their clinical and predictive value. However,
further research is still needed as the DPYD gene
is highly variable, complicating the attempts to establish
genotype-phenotype correlations. Therefore, to individualise
5-FU therapy, several integrative/complementary approaches
appear to be indicated to determine the dihydropyrimidine
dehydrogenase metabolizer status. In principle, these diagnostic
approaches in assessing dihydropyrimidine dehydrogenase activity
include genotyping and phenotyping for the DPYD.
This paper presents a critical summary and evaluation of the
current state of research on both DPYD genotyping
and phenotyping, and the pharmacogenetic syndrome of dihydropyrimidine
dehydrogenase deficiency more generally. For DPYD
based personalized medicine diagnostics to advance forward
to become standard state of the art in routine testing, we
also suggest the need for additional genetic, biological and
clinical characterization of this pharmacologically significant
variation across different global populations.
[Back to top] [Full
text article]
Economic and Cost-Effectiveness Considerations for
Pharmacogenetics Tests: An Integral Part of Translational
Research and Innovation Uptake in Personalized Medicine
D. Paci and D. Ibarreta
Across the translational research continuum from biomarker
discovery to public health research, "cost-effectiveness"
considerations are crucial, and can significantly impact the
adoption of personalized medicine innovations. Cost-effectiveness
is concerned with providing evidence to compare the (economic)
costs and the health outcomes of competing health interventions
or technologies. This also affects translational research
in all stages, including clinical trials, post-market monitoring
and population health outcome assessment. Indeed, economic
considerations are important in determining the development
and diffusion of a new technology in any scientific field.
This is particularly true in health-related sectors, wherein
governments and regulatory agencies with a mandate and commitment
to efficient and rational allocation of resources require
transparent and rigorous economic evidence to support or decline
the adoption of a new technology. In the context of personalized
medicine and theragnostics (i.e., the fusion of therapeutics
and diagnostics), the use of genomics in clinical practice
can be markedly facilitated by tandem evaluation of the clinical
benefits/risks of customized health interventions and their
cost-effectiveness. This paper provides a synthesis of the
past and emerging literature on cost-effectiveness studies
that evaluate pharmacogenetics tests. We conclude that despite
the recent efforts, there is still a scarcity of convincing
evidence on the cost-effectiveness of genomics products that
creates a barrier in the uptake of pharmacogenetics in personalized
medicine. Additionally, the reasons that limit a wider development
of the cost-effectiveness analyses in this field are discussed,
with a view to amend the above translational gaps in the literature.
[Back to top] [Full
text article]
Personalized and Predictive Medicine in Turkey: A
Symposium Report of the Istanbul Working Group on Personalized
Medicine, Istanbul, Turkey, September 10-12, 2009
Pp. 297-301
C. Hizel, S. Gök, S. Sardas, D. Bernard-Gallon, C. Maugard
and E. Genç, on behalf of the Istanbul Working Group
on Personalized Medicine
Pharmacogenetics has its roots in the 1950s with pioneering
studies of monogenic variations in drug metabolism and pharmacokinetics.
With the availability of high-throughput genomics technologies
and the completion of the Human Genome Project in 2003, we
are now in the postgenomics era. This transition is increasingly
marked with study of polygenic and multifactorial traits such
as common complex human diseases as well as pharmacodynamic
differences among populations. Changes that emerge from postgenomics
medicine are not, however, limited to seismic shifts in scale
and scope of pharmacogenetics research. Importantly, many
low- and middle-income countries (LMICs) of the South, Asia-Pacific,
Eastern Mediterranean and the Middle-East are becoming notable
contributors with rapid globalization of science and increasing
access to genomics technologies. This brings about, in parallel,
an acute demand for regional capacity building in LMICs so
that the future evaluation and implementation of postgenomics
technologies in personalized medicine take place in an integrated,
sustainable and equitable manner. With this overarching vision,
we herein report the founding of the Istanbul Working Group
in Personalized Medicine (IWG-PM, represented by the authors
of this report) that was inaugurated as a component of the
2nd Symposium on Personalized
and Predictive Medicine held in Istanbul, sponsored by the
Yeditepe University, and the Turkish Scientific and Technological
Research Council (TUBI-TAK) (10-12 September, 2009). While
highlighting the applications of personalized medicine in
oncology, psychiatry, nutrition, infectious diseases, occupational
health, genetic testing and systems biology, the symposium
also raised challenging questions in the context of LMICs.
How can we best evaluate the promises, intended and unintended
impacts of personalized medicine and enabling technologies
in the context of Turkey, and the LMICs more generally? IWG-PM
is a small but significant and necessary step to initiate
regional capacity building in Turkey. We trust that the IWG-PM
initiative may also provide a constructive example to further
develop capacity in other LMICs in the Eastern Mediterranean
region.
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