WEDNESDAY, SEPTEMBER 19
7:30-8:15 Breakfast Workshop or Morning Coffee
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METABOLIC BIOMARKER DISCOVERY
8:30-8:35 Chairperson’s Opening Remarks
8:35-9:05 Metabolomics for Mapping Disease Signatures and Drug Response Phenotypes
Rima Kaddurah-Daouk, Ph.D., Associate Professor, Department of Psychiatry and Behavioral Sciences, Duke University Medical Center
Metabolomics is the study of metabolism at the global level and involves studies of the metabolome, the entire repertoire of small molecules present in cells and/or tissues. The identities, concentrations and fluxes of these compounds represent the final product of interactions that extend from gene sequence to include gene expression, protein expression and the total cellular environment, an environment that in the clinical setting includes drug exposure. Using several targeted and random metabolomic analytical platforms and informatics tools we have started to define initial metabolic signatures for several central nervous system (CNS) disorders and for response to drugs used to treat these disorders. Metabolic signatures reveal impairments in neurotransmitter and lipid biochemical pathways and ongoing effort is underway to map more precisely sites of impairments. Additionally, we have established the National Metabolomics Consortium for Drug Response Phenotype, a consortium specifically designed to integrate metabolomics and pharmacogenomics data towards better defining drug response phenotypes. We will share initial findings from the analysis of simvastatin, a drug used for the treatment of cardiovascular disease.
9:05-9:35 Urine and Plasma Biomarkers in Schizophrenia
Stephen Furlong, Ph.D., Director, Discovery Medicine, AstraZeneca
For over fifty years reports have been appearing in the literature suggesting metabolic changes in schizophrenia patients that can be detected in urine, blood and skin. Although the existence of these changes have not been universally confirmed and have been somewhat controversial, understanding the extent of the nature of these changes could be key to understanding the pathophysiology of the disease and developing new drugs. In this talk, we will review metabolic changes associated with schizophrenia and report new data obtained with human plasma and urine samples from patients treated with two drugs compared to clinically normal individuals.
9:35-10:05 Metabolomics-Based Methods for Biomarker Discovery of Disease
Daniel Raftery, Ph.D., Professor, Chemistry, Purdue University
Recent research has shown that measurable changes in the concentration of metabolites present in biofluids can be used to develop biomarkers for early disease diagnoses. This metabolic profiling or metabolomics-based approach involves a combination of high resolution spectroscopy and multivariate statistical methods that can provide information on hundreds of metabolites in parallel, and provides the ability to cluster “disease” and “healthy” samples based on changes in the concentration of multiples of putative biomarkers. While the analysis of biofluid samples by 1D NMR and pattern recognition methods have proven effective at discriminating populations, these methods tend to focus on the metabolites with high concentration. New approaches are being developed that focus on both major and minor components to provide improved ability to discriminate similar samples. Advanced approaches for enhancing the ability of NMR for metabolic profiling with examples using both small animals and human samples will be discussed. Combining the methods of NMR and mass spectrometry (MS) provides a powerful approach to discovering and validating metabolite biomarkers. Not only can we use similar statistical approaches to analyze the MS spectra, but we can combine or correlate the results of NMR and MS to identify important changes in metabolic pathways due to disease or confounding effects such as diet. This type of metabolic network information provides insight into disease development and could be very useful ultimately for identifying drug targets.
10:05-11:00 Coffee Break with Poster and Exhibit Viewing
11:00-11:30 Comprehensive Metabolomic Approach Towards Diagnostic Tests
Vladimir Tolstikov, Ph.D., Director, Metabolomics Core, University of California, Davis Genome Center
In the previous study, we demonstrated that three independent mass spectrometry-based analytical techniques are suitable for renal cell carcinoma (RCC) malignance detection in urine. Urine contains metabolic signatures of many biochemical pathways, this bio fluid is ideally suited for metabolomic analysis, especially involving diseases of the kidney and urinary system. We will report on an extended study dedicated to biomarkers finding/validation, blind and guided data mining, lessons learned during this study, as well as from other studies using metabolomic approach with “in method validation” developed in our laboratory towards biomarkers finding/validation in biological fluids.
11:30-12:00 Metabolic Fingerprinting of Breast Cancer
Vladimir Shulaev, Ph.D., Associate Professor, Virginia Bioinformatics Institute
Metabolomics is the study of cells by measuring profiles of all, or a large number, of their metabolites. We use metabolomics approach to study the progression of malignancy of breast epithelial cells. To identify robust molecular signatures that uniquely characterize early stages of malignant transformation we employ a combination of the detailed metabolic fingerprinting with data processing using mathematical, statistical, and machine learning algorithms. Data from this approach will be presented.
12:00-1:30 Lunch (on your own)
METABOLITE BIOMARKERS OF TOXICITY
1:30-2:00 NMR Metabolomics: Metabolites, Mechanisms, and Pathways
Qiuwei Xu, Ph.D., Merck Research Laboratories
With a drive to identify novel therapeutic targets, drug development faces a demanding challenge to minimize toxicity. The application of metabolomics to toxicity screening and investigation provides a new paradigm of molecular toxicology. It can contribute to efforts to understand underlying mechanisms of toxicity and reduce failure in late stage drug development. We will discuss NMR-based metabolomics with emphasis on metabolite identification and pathway-oriented mechanistic investigations.
2:00-2:30 Characterization of Multi-Age Rodent Pediatric Models of Toxicity
Laura K. Schnackenberg, Ph.D., Staff Fellow, Division of Systems Toxicology, National Center for Toxicological Research, Food and Drug Administration
Sprague-Dawley (SD) rats (10, 25, 40, 80 days old) at ages that are equivalent to human infants, toddlers, young and mature adults were treated daily with gentamicin (50 or 100 mg/kg, s.c., for 6 or 14 days) or cisplatin (1, 3, or 6 mg/kg, s.c., 1 day) to identify potential differences in pediatric vs. adult susceptibility to renal toxicity. There was an age-dependent sensitivity to gentamicin with 10 and 80>40>25 days old and to cisplatin was 80 and 40>25 and 10 days old. The magnitude of change in gene expression level of a set of nephrotoxicity biomarkers in animals treated with gentamicin and cisplatin correlated with the extent and severity of renal pathology. The levels of urinary biomarkers of nephrotoxicity and evaluation of metabonomic data indicated a distinctly separate and unique pattern for each drug and each age group. These findings indicate that metabonomic studies in multi-age animal models could be used as a means for predicting pediatric drug safety in pre-clinical and clinical studies.
2:30-3:00 NMR-Based Metabolomics of Immunosuppressant Toxicity After Organ Transplantation
Natalie J. Serkova, Ph.D., Associate Professor, Anesthesiology and Radiology, Cancer Center MRI/MRS Core, University of Colorado Health Sciences Center
In clinical renal transplantation, four distinguished complications occur after organ transplantation: (i) delayed graft function (DGF, due to ischemia/reperfusion injury); (ii) acute rejection; (iii) chronic rejection; (iv) immunosuppressant (cyclosporine) nephrotoxicity. Using high-resolution 1H-NMR (nuclear magnetic resonance) metabolomics on urine and blood of animal models and renal recipients, metabolic markers of early graft dysfunctions versus cyclosporine toxicity were distinguished and validated. Uric acid pathway was a highly specific marker for ischemia/ reperfusion (IR) injury, in addition to a well known medulla injury marker TMAO. In contrast to IR injury after transplantation, the major immunosuppressant cyclosporine, which is known to be nephrotoxic, increased lactate and decreased glutathione blood concentrations, with slightly increased TMAO level. Due to the enormous capability of metabolomics for defining metabolic pathways and detecting metabolic biomarkers, it could soon become a reliable tool to assess graft function and to distinguish between pathophysiologies in clinical transplantation.
3:00 Close of Conference