Abstract
This conference scene outlines a selection of sessions, which deals with the field of pharmacogenomics, held at the 78th Annual meeting of the German Society for Experimental and Clinical Pharmacology and Toxicology (DGPT), which took place from 19–22 March 2012 in Dresden, Germany. The DGPT is a registered society that represents the organization of three associations: the German Society for Pharmacology (dgp), the German Society for Clinical Pharmacology and Therapy (DGKliPha) and the German Society for Toxicology (gt). The conference represents a platform for intensive dialogues within and between the different disciplines covering basic science, the identification and understanding of new drug targets, the wide field of pharmaco- and toxico-genomics, drug regulation and toxicological risk assessment, as well as future advancements of new technologies.
The conference comprised three plenary presentations, 30 sessions and symposia with a total of 151 oral presentations and was attended by approximately 800 scientists. It was opened with a presentation by Jennifer Sims (Novartis, Basel, Switzerland). Her talk entitled ‘Strategies in preclinical testing of novel biological drugs‘ gave a comprehensive overview of a very diverse range of biotechnology products for therapeutic use, including small molecules and biologics over the past centuries Citation[1]. Because of warnings about adverse consequences of immunogenicity but also warnings about malignancies such as cancer or chronic kidney disease occurring in patients treated with, for example, erythropoiesis-stimulating agents, some of the biologics had to be withdrawn from the market. One possibility to ensure the safety of the patients, one should predict the clinical effects of novel biological drugs from data generated in the preclinical phase. In this part of the talk she focused on the selection of pharmacologically relevant species in an animal model of any disease for the safety assessment of pharmaceuticals. It is essential to understand the limitation of animal species such as sequence differences or differences in cell type specificity. Jennifer Sims pointed out that better predictive models are needed for work on future challenges faced by clinical studies with better safety assessments.
In the session ‘Molecular clinical pharmacology and models of disease‘, the first speaker Andreas Böhm (University of Greifswald, Germany) presented work on ‘The release of shingosine-1-phosphate from human platelets during acute coronary syndrome‘, which is shown to be attenuated by intravenous treatment with 500 mg acetylsalicylic acid Citation[2].
Susanne Schiffmann (University of Frankfurt, Germany) highlighted the critical role of ceramide synthase 6 in the development of experimental autoimmune encephalomyelitis, the counterpart of human multiple sclerosis. The level of the ceramide (Cer) with a C16:0 N-acyl side chain (C16:0-Cer) were 1.9-fold increased in multiple sclerosis patients as well as in the lumbar spinal cord of encephalomyelitis mice and were caused by a transiently increased expression of CerS6 in macrophages, regulating the nitric oxide and TNF-α synthesis Citation[3]. In the same session Achim Schmidtko (University of Frankfurt) presented his results concerning ‘Additive antinociceptive effects of a combination of vitamin C and E after peripheral nerve injury‘. Interestingly, vitamin C or E administered alone, failed to affect the nociceptive behavior in mouse models of inflammatory and neuropathic pain, suggesting that the combination of both may exert synergistic antinociceptive effects Citation[4]. In the last presentation of the session Sierk Haenisch (University of Kiel, Germany) discussed miRNA and DNA methylation in focal and nonfocal brain tissue of therapy-resistant epilepsy patients. He compared the miRNA-expression profiles of brain tissue from patients diagnosed with mesial temporal sclerosis. Eight out of 150 miRNAs expressed in both tissues were deregulated in the hippocampus compared with the cortex and were identified to be crucial for neuronal regulation and signal transduction. These results are underlining once more the importance of epigenetic regulation of genes that are involved in giving a balance between neuronal excitation and inhibition in epilepsy patients.
A further highlight was the symposium ‘Pharmacology: the enigma of chronic pain: novel mechanistic insights and therapeutic advances‘ that was supported by the British Pharmacological Society (BPS). It started with a presentation by Michaela Kress (Medical University of Innsbruck, Austria). She focused on the G-protein-coupled receptor pathways involved in nociceptive modulation and pain processing. Investigating mice double-deficient for G-proteins such as Gaq and Ga11 she could demonstrate that Gq/11 has a functional role in G-protein signaling in nociceptors in vivo. It not only spans sensitization mechanisms in pathological pain but is also operational in tonic modulation of basal nociception and acute pain Citation[5]. Further presentations dealt with investigations on the cause of tumor pain. Rohini Kuner (University of Heidelberg, Germany) focused on cancer pain mediated via tumor nerve interaction. Since 30–40% of cancer patients suffer from chronic pain, from which 90% were due to cancer-related pain, there is a strong need for more investigations on this topic.
The first speaker of the session ‘Pharmacogenomics and Pharmacoepidemiology‘ Thomas Mürdter (Dr Margarete Fischer-Bosch Institute, Stuttgart, Germany) outlined that the ‘bioactivation of the major infertility drug chlomiphene depends on CYP2D6 polymorphisms‘. He reported that CYP2D6 revealed to be the major CYP enzyme that catalyzes the formation of the active 4-hydroxlated isoforms of chlomiphene. Data from 30 female healthy volunteers, receiving one dose of chlomiphene confirmed the in vitro results, providing a pharmacogenetic rational for the variability in response to chlomiphene treatment. Finally, Matthias Schwab from Stuttgart reported that the human pregnane X receptor (PXR) genotype of the donor but not the recipient is a risk factor for delay graft function (DGF) after renal transplantation. In a cohort of renal transplant patients, DGF occurred in 27.5% of cases. Logistic regression analysis indicated that only the donor‘s PXR 8055TT genotype (rs2276707) was significantly associated with DGF. The findings suggest that PXR may be a risk gene for the development of DGF independently from previously identified risk factors.
An exciting session topic was dedicated to ‘Frontiers in immunotherapy and vaccination‘. The first speaker Cornelis Melief (University of Leiden, The Netherlands) gave a comprehensive overview of ‘Immunotherapy of established lesions caused by high-risk human papilloma virus‘. He gave a critical view on the impact of vaccine treatment on the overall survival and remarked that the reasons for the limited response should be analyzed as well as possibilities to enhance the efficacy of therapeutic vaccines and the combination of vaccines with other anticancer treatments Citation[6].
One of the highlights of the congress was a plenary lecture given by Dan Mark Roden, (Vanderbilt University School of Medicine, TN, USA). His very inspiring presentation entitled ‘Pathways to personalized medicine‘ and started with comments on the general problem of variable drug response in patients. One example was the treatment of 38 subjects with venlafaxine and the subclassification of patients into poor and extensive metabolizers. The question he asked was: ‘Would you genotype patients before starting the therapy and when you have the data, what to do with this?‘ He continued by showing the results of a clopidogrel genome-wide association study in 429 Amish people followed by genotyping of the loss-of-function CYP2C19*2 variant (rs4244285) Citation[7]. Clopidogrel therapy is established to improve the cardiovascular outcome of patients with acute coronary syndromes following percutaneous coronary intervention by inhibiting ADP-dependent platelet activation. He concluded that CYP2C19 poor metabolizers are associated with diminished platelet response to clopidogrel treatment and less cardiovascular outcomes. Regulatory authorities acknowledged this problem by revising the label of clopidogrel in the USA in 2010 by adding a note concerning CYP2C19 poor metabolizers and recommendation of taking the proton pump inhibitor prasugrel rather than the CYP2C19 inhibitor omeprazol. The major question was ‘When is it necessary to sequence a patient? Do we preventive genotype before there is any reason to, or in a reactive way – when sequence data is necessary for therapy suggestions? Since the costs of complete genome sequencing is currently estimated to be US$10,000, it is not yet possible to sequence any patient. The next step – if the patient is genotyped – is how to store the results safely and how to make data available. Roden introduced the electronical Medical Records and Genomics (eMERGE) Network, which was announced in 2007 and should facilitate the availability and use of patients‘ data. Another important topic ‘New developments in molecular diabetes therapy‘ was introduced by Ezio Bonefacio (University of Technology, Dresden, Germany) who gave a comprehensive overview of techniques for β-cell replacement to cure diabetes. This kind of therapy has not become a routine clinical therapy so far because there are many limitations such as scarcity of proper β-cell donors, loss of the transplanted β-cells within the first few days after transplantation (poor graft survival), recurrence of the autoimmunity in some patients, and the associated loss of graft function. However, the new techniques already tested in mice showed that islet cells can be protected from outer environmental factors such as immune distraction and inflammation when cells are transferred into encapsulating devices and are transplanted into the bone marrow or muscle tissue.
Michele Solimena (University of Technology) added further new developments in diabetes. He observed that the formation of β-cell cluster results in the generation of islets and facilitates their secretion and proliferation suggesting that ICA512, a receptor of the insulin secretory granula, is a link between β-cell adhesion, insulin secretion and β-cell replication Citation[8].
Finally, within the session ‘Epigenetic mechanisms‘, Karen Lillycrop (University of Southampton, UK) gave an exciting talk focusing on epigenetic transgenerational effects. Epidemiological studies showed that a poor intrauterine environment induced by restricted maternal diet, placental insufficiency or endocrine factors induces a phenotype in the offspring, which in humans is associated with increased risk of developing chronic noncommunicable diseases Citation[9].
Conclusion
This meeting displayed a great overview of many different topics and news around experimental and clinical pharmacology and toxicology. It is becoming clear that in the future we need to think about new innovative tools to link the rapidly increasing understanding of molecular processes and their interindividual genetic and epigenetic regulation. The introduction of system biology tools and knowledge may help in this matter, but there is a tremendous need for further translational investigations from functional analysis in vitro up to clinical research for the benefit of individual patients.
Financial & competing interests disclosure
The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.
No writing assistance was utilized in the production of this manuscript.
References
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