Pharmacogenetics : the science of predictive clinical pharmacology

The study of pharmacogenetics has expanded from what were initially casual family-based clinical drug response observations, to a fully-fledged science with direct therapeutic applications, all within a time-span of less than 60 years. A wide spectrum of polymorphisms, located within several genes, are now recognised to influence the pharmacokinetics and pharmacodynamics of the majority of drugs within our therapeutic armamentarium. This information forms the basis for the new development of pharmacogenetic genotyping tests, which can be used to predict the therapeutic and/or adverse effects of a specific drug in a particular patient. Pharmacogenetic-guided, patient targeted therapy has now become the developing fulcrum of personalized medicine, as it provides the best means to optimize benefit/risk ratio in pharmacological management.peer-reviewe

Biotech drugs : biological therapeutic agents

The recent years has seen significant growth in a new therapeutic approach to the management of disease. Biological therapeutic agents, constitute a broad category of drugs, usually generated by recombinant techniques from living organisms. These therapies revolutionise the traditional approaches to drug design and development, and regulatory agencies have been swift in developing the necessary structures to ensure their optimal use.peer-reviewe

Molecular mechanisms in haematological malignancies

Haematopoiesis requires the constant production of large numbers of peripheral blood cells. This process is under tight control of transcription factor networks as well as cytokines, growth factors and hormones. We will review the importance of transcription factors in programming the haematopoietic lineage commitment and the role of the microenvironment and the corresponding cellular sensitivity to ensure production of mature functional cells in response to the physiological demand. Understanding the molecular mechanism of this complex process gives the opportunity to identify the underlying molecular deregulation in haematopoietic malignancies. The different levels of deregulation include hyperproliferation, block in differentiation and sensitivity to growth factors. In this review, leukaemic transformation is selected to give evidence of cell signalling deregulation. The clinical implications will be reviewed in the context of the potential opportunities in the future to identify specific therapeutic patient groups that can be defined using prognostic and predictive biomarkers.peer-reviewe

Actionable pharmacogenetic markers for prediction and prognosis in breast cancer

We would like to thank Professor Christian Scerri for advice and constructive discussions.Breast cancer is a heterogeneous disease that necessitates proper patient classification to direct surgery, pharmacotherapy, and radiotherapy. Despite patients within the same subgroup receiving similar pharmacotherapy, substantial variation in clinical outcomes is observed. Pharmacogenetic variations with direct effect on pharmacokinetics and pharmacodynamics play a central role in clinical outcomes. Pharmacogenetic markers associated with clinical outcome are known as biomarkers. They are termed prognostic biomarkers when their presence is associated with a specific clinical outcome. If the presence of such biomarkers guides treatment, they are termed predictive biomarkers. A number of pharmacogenetic markers have been described in relation to breast cancer pharmacotherapy both in the adjuvant and neoadjuvant setting. CYP2D6 allelic variants produce variable rates of tamoxifen metabolism and are associated with survival outcomes. Other biomarkers have been described in relation to other forms of endocrine therapy and trastuzumab. In neoadjuvant and adjuvant breast cancer chemotherapy, specific biomarkers were correlated with clinical outcomes and risk of drug toxicity. This review highlights key biomarkers in breast cancer pharmacotherapy with the potential of translating such study outcomes into clinical practice.peer-reviewe

Molecular classification of colorectal cancer

Colorectal cancer (CRC) is a heterogeneous disease with several clinical, pathological, and molecular presentations. A comprehensive and unifying molecular classification would be useful for genotypephenotype correlations, to better understand disease progression, and to predict responses to treatment. Such a classification would be helpful for quickly and efficiently translating results from the laboratory to the clinic and closing the gap between research breakthroughs and actually implementing them clinically. In November 2015, an international consortium consisting of six expert groups published the first consensus on molecular subtypes of colorectal cancer, by bringing together six previously published CRC classifications.peer-reviewe

Pharmacogenetics and personalized medicine : does gender have a role?

The study of the role of genetic polymorphisms in drug responses, is now a firmly established field of pharmacology research. It has robust applications in predicting drug effect, and therefore contributes to the process of optimum selection of drug and dose for specific patients. Since the last 10 years, the FDA as well as the EMA have set up their own pharmacogenomics advisory groups, and have flagged an increasing number of medicinal products with specific genotyping recommendations in order to reap their greatest benefit. The contribution of gender to therapeutic outcomes has long been recognised, but recent research suggests that gender influence may not only occur via well recognised hormonal pathways, but also via direct non-hormone-mediated mechanisms. This influence may confound pharmacogenetic predictors, and gender stratification may therefore be an important consideration in pharmacogenetic-based drug trials.peer-reviewe

Biotech drugs : biological therapeutic agents

The recent years has seen significant growth in a new therapeutic approach to the management of disease. Biological therapeutic agents, constitute a broad category of drugs, usually generated by recombinant techniques from living organisms. These therapies revolutionise the traditional approaches to drug design and development, and regulatory agencies have been swift in developing the necessary structures to ensure their optimal use.peer-reviewe

Pharmacogenetics : where do we stand?

“Our drugs do not work on most patients.” Such did Allen Roses, then worldwide vice-president of genetics at GlaxoSmithKline, greet his audience, during a scientific meeting in London in 2003.1 Nearly a decade has passed since then, and significant strides towards the development of genotype-guided prescribing have been made. Pharmacogenetics and pharmacogenomics are now an established area of pharmacology specialization, and they hold the promise of the key to personalized medicine, leading to safer and more effective patientfocussed therapeutic outcomes.peer-reviewe

The Role of Translation Initiation Regulation in Haematopoiesis

Organisation of RNAs into functional subgroups that are translated in response to extrinsic and intrinsic factors underlines a relatively unexplored gene expression modulation that drives cell fate in the same manner as regulation of the transcriptome by transcription factors. Recent studies on the molecular mechanisms of inflammatory responses and haematological disorders indicate clearly that the regulation of mRNA translation at the level of translation initiation, mRNA stability, and protein isoform synthesis is implicated in the tight regulation of gene expression. This paper outlines how these posttranscriptional control mechanisms, including control at the level of translation initiation factors and the role of RNA binding proteins, affect hematopoiesis. The clinical relevance of these mechanisms in haematological disorders indicates clearly the potential therapeutic implications and the need of molecular tools that allow measurement at the level of translational control. Although the importance of miRNAs in translation control is well recognised and studied extensively, this paper will exclude detailed account of this level of control

The re-emergence of the B1 cell compartment : is this a pre-lymphoma stage?

Chronic Lymphocytic Leukemia (CLL) are in some cases stereotyped for immunoglobulin variants in different populations, suggesting emergence of B cell subsets following presentation of the same antigen. CLL cells may originate from CD5+ naïve cells and from CD5 memory cells. Gene expression studies characterized a common cell of origin of the two clinical categories of CLL; the unmutated aggressive type and the mutated indolent type. The aim of this study was to investigate the presence of CD5 positive B cells in the elderly and their potential stimulation with exosomes derived from tumor cells. The findings from this study is aimed to create a model to identify instigating carcinomatous factors that may stimulate B1 cells to transform into a CLL-like model. In this study we show that CD19\textsuperscript+ cells (B cells) in cord blood have a high expression of CD5. CD19/CD5 staining of blood samples from senior citizens showed the presence of B cells which also express the CD5 marker, though at a lower expression when compared to CLL cells (CD19+/CD5 dim B cells). Measurement of clonality using λ/Κ flow cytometry staining show a monoclonal origin of the human CD19+/CD5 dim B cells. Monoclonal B cell Lymphocytosis in the elderly is a potential cell compartment that represents the origin of B cell proliferative disorders. The origin of the B cell proliferative disease requires antigen stimulation. A preliminary experiment showed that sorted lymphocytes can be stimulated by exosomes isolated from 2 cancer cells lines, A549 (lung epithelial) and PC3 (prostate cell line). In comparison with phytohaemagglutinin (PHA) and phorbolmyristate acetate (PMA), known lymphocyte stimulators, the exosomes stimulated the proliferation of monocytic-like cells. Further characterization is required to know the origin of these cells. The result shows that one can speculate that exosomes present cancer-derived antigens and stimulate cell proliferation. Further studies are required to evaluate the potential transformation capacity of cancer-derived exosomes. In addition, various cytokines were measured in the sera of senior citizens to investigate a differential release of cytokines in the presence or absence of the CD19+/CD5 dim B cells. Cytokines examined were not significantly different between the 2 groups and further evaluation of cytokine levels is required.peer-reviewe