Current Pharmacogenomics and Personalized Medicine (Formerly Current Pharmacogenomics) - Volume 7, Issue 1, 2009

The statins are the most important group of drugs for lipid-lowering therapy in the prevention of coronary heart disease. Greater reductions in LDL-cholesterol appear to be associated with greater benefits but the clinical efficacy and safety of statin treatment varies considerably from person to person because of a combination of phenotypic and genotypic factors. Pharmacogenetic studies have investigated the relationship between common genetic variants and the lipid responses to statin therapy and adverse events, and some candidate genes related to the pharmacodynamics and pharmacokinetics of different statins have been identified. Some of these genetic variants show a different frequency in different ethnic groups. This field of pharmacogenetic research is receiving considerable attention and many new findings have been reported recently. Pharmacogenetic and pharmacogenomic studies of statin therapy are likely to provide a better understanding of the effects of these drugs and to help with prediction of the most appropriate drug and dosage for each individual and whether the addition or substitution of other lipid modifying drugs may be necessary to achieve the most safe and effective prevention of coronary heart disease.

Cancer cells continuously adapt to their local and external milieu during their growth by acquiring new biochemical and cellular properties. For example, in many cancer cells, glycolytic capacity increases even in non-hypoxic conditions. The latter phenomenon is known as ‘aerobic glycolysis’ and has become a central topic in the field of cancer biology. Aerobic glycolysis is induced by several factors including dysfunction of mitochondria. The cells with the dysfunction of the oxidative phosphorylation (OXPHOS) increase production of reactive oxygen species (ROS) that can activate some signaling proteins and induce mutations in oncogenes and tumor suppressor genes. Dysfunction of the enzymes in the Krebs cycle may impact activity of transcription factors such as HIF1α through changes in the amount of the organic acids in the cycle. Study of the mitochondria function also reveals important insights on JmjC-domain proteins, which demethylate histones and therefore control gene expression. The oncogene myc, which is widely overexpressed in cancer cells, induces the expression of genes involved in mitochondrial ATP production. Collectively, there is emerging evidence supporting the idea that the machinery involved in mitochondrial ATP production can serve as a ‘pathway target’ for development of diagnostic tests to evaluate behaviors of human cancers, and to identify novel drug targets that may be critical for treatment of molecular subtypes of cancers. This expert review presents a synthesis of the recent advances in our understanding of the mitochondrial dysfunction and ATP production, and ways in which this knowledge may translate into personalized cancer therapeutics and diagnostic tests.

The ATP-Binding-Cassette (ABC) superfamily of transporters, implicated in the traffic of drugs/xenobiotics across membranes, represents one of the larger families of drug-response genes. Many of these transporters are expressed at apical membranes of barrier tissues where they offer protection against orally ingested or airborne toxins. They can also modulate the absorption of orally administered drugs to influence drug-disposition. Hence, genetic polymorphisms at these genes may account, in part, for inter-individual variation in drug-response. With the identification of an increasing number of polymorphisms even for individual genes, it has become increasingly difficult to associate polymorphisms at these gene loci with drug-response due to increased Type I error if all SNPs in these genes are examined. It is therefore worthwhile and timely to identify a subset of SNPs at the ABC gene loci that have potential functional significance to facilitate future association studies. In this review, we describe approaches that are being adopted to rationally select a subset of SNPs for association studies including the tagging-SNP strategy as well as strategies to identify SNPs of potential functional significance either through population-genetics, evolutionary or structural approaches. In addition, databases were mined to identify SNPs in the ABC gene loci that may have potential significance. Finally, the literature was also mined for SNPs at the ABC gene loci that were previously reported to be associated with drug-response or other phenotypes. The value of these SNPs in facilitating the ushering of the era of personalized medicine will be discussed.

In recent years the design of association studies published in pharmacogenetics journals has markedly changed and the corresponding analyses have increasingly involved a large number of SNPs, genes and patients, and a transition from the candidate gene strategy to the whole-genome association (WGA) studies. This review provides an overview of the recent advances that have led to this transition, lists the advantages and disadvantages of both strategies, candidate genes and WGA, and discusses their applicability. Another area in need of development is the standards to validate the pharmacogenetics associations observed to date. To this end, pharmacogenetics studies can also be classified as exploratory or confirmatory, independent from the design strategy used. This review discusses the importance of both types of study, exploratory and confirmatory, in ongoing efforts to replicate significant associations, and in order to provide adequate evidence for the introduction of pharmacogenetics tests in clinical practice. These different strategies or objectives (candidate genes versus WGA; exploratory versus confirmatory) are valid approaches to achieve the ultimate goal of pharmacogenetics, personalized medicine. Additionally, these nuanced differences in pharmacogenetics scientific practice must be kept in mind to ensure the appropriate evaluation of scientific merit in pharmacogenetics association studies, and their appropriate differentiation from the genetic studies concerning the disease susceptibility phenotypes.

Colorectal cancer is the second most common malignancy in the U.S. In the past 15 years we witnessed the development of new anticancer agents for patients with colorectal cancer. A multitude of therapeutic options creates a challenge for a physician to select the most efficacious and least toxic agent for an individual patient. To this end, pharmacogenomic variability in metabolic pathways for fluorouracil, capecitabine, irinotecan and oxaliplatin has been characterized. Pharmacogenomic investigations of dihydropyrimidine dehydrogenase, thymidylate synthase and thymidine phosphorylase identified a panel of clinically relevant polymorphisms for fluoropyrimidine drugs. Polymorphisms in nucleotide excision repair genes such as ERCC1 can modulate oxaliplatin exposure. For irinotecan, a polymorphism of the uridine diphosphate glucuronosyltransferase increases the risk for neutropenia. The pharmacogenomic test for this variation (UGT1A1*28) is approved by the FDA for patients who are candidates for irinotecan therapy. Disposition and activity of targeted agents, such as therapeutic antibodies bevacizumab and cetuximab, are influenced by additional genomic variations. Deficient nucleotide mismatch repair system, a hallmark of hereditary colon cancer syndrome (identified as high frequency microsatellite instability), emerged as a predictive marker for 5-fluorouracil in the adjuvant setting and the KRAS mutation as a determinant of sensitivity to anti-EGFR antibodies. Collectively, these advances establish a firm basis towards future development of an integrated pharmacogenomics array for prime time applications in the clinic to customize pharmacotherapy for colorectal cancer. We also emphasize that individualizing anticancer chemotherapy is an arduous task because drug efficacy and toxicity represent multifactorial complex traits mediated by multiple DNA sequence variants, temporal variations in gene expression, environmental factors and gene-environment interactions.