Current Pharmacogenomics and Personalized Medicine (Formerly Current Pharmacogenomics) - Volume 6, Issue 4, 2008

Pharmacogenetics/-genomics (PGx) was a major topic of the XI edition of the Sao Paulo Research Conferences (SPRC, 18-20 September, 2008), sponsored jointly by the Sub-Committee on Pharmacogenetics of the International Union of Basic and Clinical Pharmacology (IUPHAR) and the Brazilian Pharmacogenetics Network (Refargen), in collaboration with the University of Sao Paulo, Brazil. Conceived as a series of meetings to explore the frontiers of knowledge in medicine, biology and social sciences, the SPRC covered in previous editions a broad range of topics, such as Cancer, Drug Addiction, Evolution and the Origin of Life, Infections and Vaccines, Memory, and Molecular Biology. The PGx program of the XI SPRC comprised a keynote lecture on Clinical aspects of pharmacogenetics: Promises and future, four symposia, poster exhibits and an oral communication session. Two symposia focused on PGx in clinical practice, and covered recent developments in the PGx of analgesics, cancer chemotherapy, anti-HIV drugs, statins and oral anticoagulants. The two other symposia focused on PGx in special populations (pediatric patients, Amerindians, Hispanic populations and admixed populations), ethical aspects of PGx and recent developments in the PGx of CYP450 drug metabolizing enzymes and drug transporters. The IUPHAR Sub-Committee on Pharmacogenetics met at the last day of conference and it was unanimously agreed that the conference format provided a valuable model for future educational initiatives of the committee. Finally, the launching of an online pharmacogenetics database for the Brazilian population at Refargen´s internet site (www.refargen.org.br) was announced at the conference.

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.

The main goal of pharmacogenomics is to study the effects of genetic variation on patient responses to therapies. Its applications range from the evaluation of safety and efficacy of treatment to the optimization of therapies and therapeutic regimens. Pharmacogenomics is becoming increasingly important in immunology, for the development of new generation vaccines, immunotherapies and transplantation. The human immune system is a complex and adaptive learning system which operates at multiple levels: molecules, cells, organs, organisms, and groups of organisms. Immunologic research, both basic and applied, needs to deal with this complexity. We increasingly use mathematical modeling and computational simulation in the study of the immune system and immune responses. Thus, quantitative models that appropriately capture the complexity in architecture and function of the immune system are an integral component of the personalized medicine efforts. In silico models of the immune system can provide answers to a variety of questions, including understanding the general behavior of the immune system, the course of disease, effects of treatment, analysis of cellular and molecular interactions, and simulation of laboratory experiments. We herein present the ImmunoGrid project that integrates molecular and system level models of the immune system and processes for in silico studies of the immune function. The ImmunoGrid simulator uses Grid technologies, enabling computational simulation of the immune system at the natural scale, perform a large number of simulated experiments, capture the diversity of the immune system between individuals, and provide a basis for therapeutic approaches tailored to the individual genetic make-up.

Cutaneous malignant melanoma represents one of the most aggressive human cancers with high metastatic potential. Differences in the response and toxicity to current melanoma therapies among individuals are observed in nearly all-available treatment regimens. The first step toward personalized medicine is identifying a panel of biomarkers that allow classification of melanoma patients for appropriate treatment and prediction of probable response to therapy. The traditional approach to biomarker detection relied on studying a few candidate markers suspected of affecting clinical outcome. However, these studies have yielded contradictory results because of the small number of molecular determinants examined. This has been a major limitation of translational studies in malignant melanoma. Recent studies using highthroughput technologies, such as gene expression profiling and serum proteomic fingerprinting, have explored the utility of molecular markers to discriminate between clinical stages and predict disease progression in melanoma patients. This expert review highlights key approaches for the discovery and validation of biomarkers at the levels of DNA, RNA and protein. It also summarizes biomarker work performed by less invasive approaches, i.e., RT-PCR in detection of circulating melanoma cells and serum markers that may be used to monitor early response to treatment and guide the therapeutic strategy. We anticipate that pharmacogenomics will play an integral role in disease assessment, patient selection and treatment response in melanoma clinical management with the ultimate goal of individualizing treatment and improving overall survival for patients.

Growth hormone (GH) promotes height growth by stimulating bone and cartilage cell proliferation, and influences carbohydrate and lipid metabolism through a direct stimulatory effect by GH, and an indirect effect mediated by insulin- like growth factor 1 (IGF-1). The effects of GH are mediated by the interaction between GH and the GH receptor (GHR). In response to GH, two GHR polypeptides form dimers and turn on a cascade of signal transduction leading to activation of gene transcription. The mechanisms of marked patient-to-patient variability in response to GH have remained elusive thus far. Recent pharmacogenetics studies suggest that the growth promotion by GH treatment is influenced by a variation in the human GHR gene (d3/fl-GHR) in patients who have been diagnosed to be small for gestational age, with GH-deficiency (GHD), idiopathic short stature, or Turner syndrome, although this genetic effect still remains controversial. Another report demonstrated the Leu544Ile SNP of the GHR gene to be associated with cholesterol levels during GH treatment in patients with GHD. This paper provides a critical overview and synthesis of the emerging findings on the GHR polymorphisms in relation to GH responsiveness or disease susceptibilities, and the attendant molecular aspects of the characteristic polymorphisms. The potential clinical application of GHR genetic variation is discussed for the optimization of the GH dosage in children or adults in order to enable them to reach their ideal final height as well as to prevent cardiovascular complications.

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.