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OPEN ACCESS PLUS
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Contents
10(4): Pp. 277 - 287
Y. W. Francis Lam
[Open Access Plus] |
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Predicting individual response to drug therapy has long been a goal of personalized medicine in every therapeutic area. The mapping of the human genome and subsequent advancements in genetic technology had raised the public expectation that personalized drug therapy would come sooner than later. However, with barriers and logistical challenges existing at multiple levels, achieving this goal remains years away. Knowledge gap in healthcare professionals has always been cited as a significant barrier in clinical implementation of pharmacogenomics. Yet, to overcome the spectrum of challenges and for personalized medicine to succeed, there needs to be a rethinking of expanding the educational scope to include all stakeholders within the personalized medicine innovation ecosystem, rather than “narrowly” focusing on simply educating current and future health practitioners. Personalized medicine can only be achieved with all stakeholders in the field, under the rubric of a vision of a “knowledge ecosystem”, working together, and occasionally accepting a paradigm change in their current approaches to implementation. If postgenomics personalized medicine is to embrace systems pharmacology as a core tenet, it seems essential that such broader vision should be extended to field of education as well.
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10(3): Pp. 217 - 225
Fatima Ghaddar, Karim Saba and Nathalie K. Zgheib
[Open Access Plus] |
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Research in the field of pharmacogenetics (PGx) has been growing exponentially over the past decade in a manner that is disproportionate to the rate of its incorporation into clinical practice. That is why efforts to further PGx education in health professional schools have been initiated to reduce the gap that currently exists between research and practice. Because there is a current paucity of information regarding the status of PGx education in low and middle income countries (LMICs) in comparison to high income countries, the aim of our study was to evaluate this important gap using an online survey that we electronically sent to the relevant delegates of the International Union of Basic and Clinical Pharmacology (IUPHAR) “World Pharma 2010” meeting (Copenhagen, July 2010). Respondents from 25 global institutions answered our survey, of which more than half had already incorporated PGx teaching into their curricula. Although PGx was an integral part of the World Pharma 2010 topics, only few PGx abstracts from LMICs were presented when compared to high income countries: 37 abstracts from 18 high income countries compared to 20 from 16 LMICs (Brazil, Chile, Croatia, Cuba, Iran, Lebanon, Montenegro, Romania, Russia, Serbia, Thailand, Trinidad and Tobago, Tunisia, Turkey, and Uganda). PGx education was mainly introduced as part of the already existing pharmacology courses, was dedicated an average of 2-4 hours of teaching, and was mainly delivered through lectures and seminars. Even though these findings are on par with the international guidelines that outline the minimal requirements of PGx education in health professional schools, further strategic planning for PGx education is no doubt crucial which can be informed by our findings reported herein. This research paper presents a discussion and concrete ways forward for teaching PGx for global personalized medicine in LMICS and beyond. To the best of our knowledge, our study provides one of the first empirical insights into the current status of PGx teaching in LMICs.
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10(3): Pp. 182 - 184
Christopher Reist, Jogeshwar Mukherjee and Joseph C. Wu
[Open Access Plus] |
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9(4): Pp. 299 - 322
Murielle Bochud, Michel Burnier and Idris Guessous
[Open Access Plus] |
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Pharmacogenomics is a field with origins in the study of monogenic variations in drug metabolism in the 1950s. Perhaps because of these historical underpinnings, there has been an intensive investigation of ‘hepatic pharmacogenes’ such as CYP450s and liver drug metabolism using pharmacogenomics approaches over the past five decades. Surprisingly, kidney pathophysiology, attendant diseases and treatment outcomes have been vastly under-studied and under-theorized despite their central importance in maintenance of health, susceptibility to disease and rational personalized therapeutics. Indeed, chronic kidney disease (CKD) represents an increasing public health burden worldwide, both in developed and developing countries. Patients with CKD suffer from high cardiovascular morbidity and mortality, which is mainly attributable to cardiovascular events before reaching end-stage renal disease. In this paper, we focus our analyses on renal function before end-stage renal disease, as seen through the lens of pharmacogenomics and human genomic variation. We herein synthesize the recent evidence linking selected Very Important Pharmacogenes (VIP) to renal function, blood pressure and salt-sensitivity in humans, and ways in which these insights might inform rational personalized therapeutics. Notably, we highlight and present the rationale for three applications that we consider as important and actionable therapeutic and preventive focus areas in renal pharmacogenomics: 1) ACE inhibitors, as a confirmed application, 2) VDR agonists, as a promising application, and 3) moderate dietary salt intake, as a suggested novel application. Additionally, we emphasize the putative contributions of gene-environment interactions, discuss the implications of these findings to treat and prevent hypertension and CKD. Finally, we conclude with a strategic agenda and vision required to accelerate advances in this under-studied field of renal pharmacogenomics with vast significance for global public health.
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9(4): Pp. 252 - 263
Edward S. Dove
[Open Access Plus] |
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In 2011, genetic privacy bills were introduced in two US states proposing that genetic information and material are an individuals exclusive property. Using the bills as a catalyst for broader discussion, the author introduces several themes. On a primary level, the scientific, medical, and broader community should be cognizant of the bills as they may be precursors to new legislation with potential future impact on genomics and personalized medicine. Their privacy-through-property approach contains definitional ambiguities (such as using the legal phraseology of “real property”), erects barriers to research and innovation, differs conceptually and procedurally from current genetic privacy legislation, and could herald a return to reductionist genetic exceptionalism. Since genetic research and personalized medicine operate in a borderless (transnational) world where natural and social system divisions are highly porous, patchwork legislation can impede advancement of knowledge transfer, health outcome delivery, and international harmonization and coordination. While these are US bills, they can set precedence with potential traction in globally networked innovation ecosystems that share, and are shaped by, legislation and international norms. Too often, law and science are artificially situated in silos. Yet law is not a disembodied system of ideas; it is a corpus embedded in a larger social structure that includes science and personalized medicine. Broader elements of society must be engaged and educated from the earliest stage of legal reform so that future legislation that impacts genomics and personalized medicine can be steered in a form more closely tuned to social values and the lessons learned from the past history of genetic/genomics research.
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9(3): Pp. 191 - 207
Louise Warnich, Britt I. Drogemoller, Michael S. Pepper, Collet Dandara and Galen E.B. Wright
[Open Access Plus] |
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South Africa, like many other developing countries, stands to benefit from novel diagnostics and drugs developed by pharmacogenomics guidance due to high prevalence of disease burden in the region. This includes both communicable (e.g., HIV/AIDS and tuberculosis) and non-communicable (e.g., diabetes and cardiovascular) diseases. For example, although only 0.7% of the worlds population lives in South Africa, the country carries 17% of the global HIV/AIDS burden and 5% of the global tuberculosis burden. Nobel Peace Prize Laureate Archbishop Emeritus Desmond Tutu has coined the term Rainbow Nation, referring to a land of wealth in its many diverse peoples and cultures. It is now timely and necessary to reflect on how best to approach new genomics biotechnologies in a manner that carefully considers the public health needs and extant disease burden in the region. The aim of this paper is to document and review the advances in pharmacogenomics in South Africa and importantly, to evaluate the direction that future research should take. Previous research has shown that the populations in South Africa exhibit unique allele frequencies and novel genetic variation in pharmacogenetically relevant genes, often differing from other African and global populations. The high level of genetic diversity, low linkage disequilibrium and the presence of rare variants in these populations question the feasibility of the use of current commercially available genotyping platforms, and may partially account for genotypephenotype discordance observed in past studies. However, the employment of high throughput technologies for genomic research, within the context of large clinical trials, combined with interdisciplinary studies and appropriate regulatory guidelines, should aid in acceleration of pharmacogenomic discoveries in high priority therapeutic areas in South Africa. Finally, we suggest that projects such as the H3Africa Initiative, the SAHGP and PGENI should play an integral role in the coordination of genomic research in South Africa, but also other African countries, by providing infrastructure and capital to local researchers, as well as providing aid in addressing the computational and statistical bottlenecks encountered at present.
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9(3): Pp. 184 - 190
Anatasha Crawford and Rita Nahta
[Open Access Plus] |
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Acquired resistance to Herceptin is a major clinical problem in the treatment of HER2-overexpressing breast cancer. Understanding the molecular mechanisms leading to resistance will allow identification of novel therapeutic targets and predictors of therapeutic response. To this end, up-regulation of anti-apoptotic proteins has been associated with resistance to the HER2-targeted drug lapatinib, but has not yet been linked to Herceptin resistance. The aim of the current study was to determine if the Bcl-2 anti-apoptotic protein is a potential therapeutic target in cells with acquired Herceptin resistance. The BT474 HER2-overexpressing breast cancer cell line and BT474-derived acquired Herceptinresistant clones were used as models in this study. Bcl-2 and Bax expression were assessed by Western blotting. Proliferation assays were performed on cells treated with the Bcl-2 inhibitor ABT-737 in the absence or presence of Herceptin. Finally, the effect of PI3K inhibition or IKK inhibition on Bcl-2 expression and Herceptin sensitivity was examined by Western blotting and established proliferation assays. We show that cells with acquired resistance to Herceptin have an increased Bcl-2:Bax ratio. Resistant cells have increased sensitivity to ABT-737. Further, pharmacologic inhibition of Bcl-2 improved sensitivity to Herceptin in acquired resistant cells. Finally, PI3K and IKK inhibition downregulated Bcl-2 expression and increased sensitivity to Herceptin in resistant cells. Taken together, these new observations support further study of Bcl-2-targeted therapies in Herceptin-resistant breast cancers, and importantly, future investigation of Bcl-2 expression as a potential predictor of Herceptin response in patients with HER2-overexpressing breast cancer.
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7(4): Pp. 263 - 274
R. Nahta, S. Shabaya, T. Ozbay and D. L. Rowe
[Open Access Plus] |
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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.
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7(3): Pp. 158 - 163
M. J. Khoury
[Open Access Plus] |
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Muin J. Khoury, MD, PhD is the first and current director of the Office of Public Health Genomics at the Centers for Disease Control and Prevention (CDC) in the United States. The Office was formed in 1997 to assess the impact of advances in human genetics and the Human Genome Project on public health and disease prevention. As an internationally recognized institution, CDCs mission is to protect the health and safety of people, to provide credible information to enhance health decisions, and to promote health through strong national and international partnerships. For more than a decade, the CDCs Office of Public Health Genomics played an important role in development of a new hybrid field of investigation, ‘public health genomics’. In the September 2009 issue of the Current Pharmacogenomics and Personalized Medicine (CPPM), Dr. Khoury shares his thoughts and immediate and long term vision on public health genomics, and why this new field of investigation is important for personalized medicine and global health. He is interviewed by a multidisciplinary team of researchers and educators: Abdallah S. Daar (McLaughlin-Rotman Centre for Global Health and School of Public Health Sciences, University of Toronto), Serge Dubé (Department of Surgery and Faculty of Medicine, University of Montreal) and Vural Ozdemir (Editor, CPPM, and Department of Social and Preventive Medicine, Faculty of Medicine, University of Montreal). Dr. Khoury received his BS degree in biology/chemistry from the American University of Beirut, Lebanon, and his medical degree and pediatric training from the same institution. He received a PhD in human genetics/genetic epidemiology and training in medical genetics from The Johns Hopkins University. Dr. Khoury is board-certified in medical genetics.
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6(4): Pp. 302 - 319
Takahiro Yoshikawa and Hiroshi Kanazawa
[Open Access Plus] |
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Genetic variability in molecular drug targets is increasingly recognized in the treatment of bronchial asthma and chronic obstructive pulmonary disease (COPD). The long-acting β2 adrenoreceptor (β2AR) agonists and long-acting muscarinic acetylcholine receptor (mAChR) antagonists have been widely used as bronchodilatory therapies in these clinical indications. These treatments are, however, far from ideal and display limited efficacy, particularly in COPD. Specific guidelines on how best to customize therapeutic regimens for individual patients are yet to be formulated. The polymorphisms within the coding block of the β2AR gene are strongly associated with receptor function and affect the long-term response to β2AR agonists in patients with asthma. Two pertinent drug target receptor subtype families, mAChRs and β2ARs, belong to the common seven-transmembrane spanning family of guanine nucleotide-binding protein (G protein)-coupled receptors (GPCRs). Cell biology studies indicate that biosignals from one GPCR can modify another receptor function through intracellular signaling and molecular cross-talk. Thus, it is conceivable that gene-gene (epistatic) interactions between these two receptors may occur, modifying the bronchodilatory response to drugs acting at these molecular targets. In accordance with this, our recent empirical observations suggest that the β2AR genotypes may influence differential bronchodilatory response to anticholinergic agents in patients with COPD and asthma. This review aims to highlight (1) the pharmacogenetic associations of β2AR gene variants with drug response in patients with asthma and COPD and (2) the importance of considering gene-gene interactions for personalization of drug therapy and the value of ‘pathway pharmacogenetics’ more generally.
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6(4): Pp. 239 - 259
Stephanie L. Nott, Yanfang Huang, Brian R. Fluharty, Anna M. Sokolov, Melinda Huang, Cathleen Cox and Mesut Muyan
[Open Access Plus] |
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Estrogen hormones play critical roles in the regulation of many tissue functions. The effects of estrogens are primarily mediated by the estrogen receptors (ER) α and β. ERs are ligand-activated transcription factors that regulate a complex array of genomic events that orchestrate cellular growth, differentiation and death. Although many factors contribute to their etiology, estrogens are thought to be the primary agents for the development and/or progression of target tissue malignancies. Many of the current modalities for the treatment of estrogen target tissue malignancies are based on agents with diverse pharmacology that alter or prevent ER functions by acting as estrogen competitors. Although these compounds have been successfully used in clinical settings, the efficacy of treatment shows variability. An increasing body of evidence implicates ERα polymorphisms as one of the contributory factors for differential responses to estrogen competitors. This review aims to highlight the recent findings on polymorphisms of the lately identified ERβ in order to provide a functional perspective with potential pharmacogenomic implications.
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6(2): Pp. 108 - 120
Catherine Olivier, Bryn Williams-Jones, Beatrice Godard, Barbara Mikalson and Vural Ozdemir
[Open Access Plus] |
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US Senator Barack Obama recently proposed the Genomics and Personalized Medicine Act of 2006, which should it be enacted, would establish a Genomics and Personalized Medicine Interagency Working Group to coordinate personalized medicine efforts, fund genomics research to improve drug safety and establish a US Biobanking Research Initiative similar to efforts deployed in other countries. But what impact could personalized medicine have on the drug development process, the pharmaceutical industry and international health, including that in developing countries? Can personalized medicines support innovation, sustainability and growth in the pharmaceutical industry and also respond to changing world realities, emerging public demands for safer and more efficacious medicines and equitable access to pharmaceuticals? The present paper examines these socio-ethical and science policy questions by first elucidating their intrinsic and often complex interactions with other economic and policy issues (and the often divergent interests of stakeholders). We then present some examples from other industries (e.g., the case of hybrid cars and attendant growth of consumer interest and confidence in high quality sustainable products), with a view to identifying the factors that might contribute to a successful integration of pharmacogenomics and related biomarker technologies in patient care, international health and public policy. In particular, we propose ways to integrate the concept of sustainability into corporate and investor models of pharmaceutical industry development. While the power of pharmacogenomics to serve as a driver for the pharmaceutical industry remains to be evaluated, we submit that biomedical innovation and economic prosperity can co-exist with ethical drug development and the sustainable commercialization of customized drug therapies.
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