Metabolomics Moving Towards A Better Understanding of Desmoid Tumors Kelly Mercier, Ph.D NIH Eastern Regional Comprehensive Metabolomics Resource Core at RTI International RTI International is a registered trademark and a trade name of Research Triangle Institute. www.rti.org
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Notable Achievements Taxol and camptothecin Speech processing for cochlear implants Survey technology (ACASI) Wind shear avoidance system Indoor air quality research Neglected tropical disease control Clean coal technology Malaria, HIV, and tuberculosis prevention and treatment programs
Metabolomics Metabolomics involves the analysis of the low molecular weight complement of cells, tissues, or biological fluids. Metabolomics makes it feasible to uniquely profile the biochemistry of an individual or system. Metabonomics is used to determine the pattern of changes (and related metabolites) arising from disease, dysfunction, disorder, or from the therapeutic or adverse effects of xenobiotics Mammalian, plant, and aquatic species This leading-edge method has come to the fore to reveal biomarkers for the early detection and diagnosis of disease, to monitor therapeutic treatments, and to provide insights into biological mechanisms.
NIH Common Fund Metabolomics Cores NIH Metabolomics Centers Ramp Up November 4, 2013 Issue - Vol. 91 Issue 44 Chemical & Engineering News. by Jyllian Kemsley
Research Collaborations Investigational Areas Treatment Intervention Nutrition Fat, Soy, Casein, Rice Exposure Metals, PAHs, Wood Smoke, PM2.5 Mental Health Schizophrenia, Bipolar Disorder, Anxiety Development Reproduction Cancer Climate Change Barth Syndrome Infection Opthamology Sample Types Kidney Liver Brain Ovary Eye Lung Muscle Serum Plasma Feces Urine Saliva Mussel Rice Sample Origin Humans Elderly Adults Children Neonates Pregnancy Animal models Primates Rodents Aquatic Insects Cells
Women s and Children s Health Pediatric Glomerular Disease Bill Smoyer Neonatal Acute Kidney Injury Pat Brophy David Askenazi Barth Syndrome Hilary Vernon Arsenic, in utero exposure, diabetes Rebecca Fry PAH, in utero exposure, birth outcomes, MDI Fredrica Perea Pregnancy Complications Michelle Williams Phthalates and Pediatric Obesity Leo Transnade New award Childhood Infections Margaret Karagas New award Pediatric Obesity David Collier in utero exposure, obesity Catherine Hoyo
Desmoid Tumor Cell Lines Dr. Ben Alman (Duke University) and the Desmoid Collaboration for a Cure Dr. Ben Alman Desmoid Collaboration for a Cure Progress: Screened 9 primary cell lines 5 different compound libraries 45 compounds inhibited cell proliferation in desmoid tumors by greater than 50% with no effect on normal fibroblast proliferation All either approved for use in patients or have the potential to be rapidly developed for patient care. Mushriq Al- Jazrawe RTI has initiated a collaboration with Dr. Alman and his group
Metabolomics Meets Desmoid Tumors Novel Therapeutics Use broad spectrum and targeted metabolomics to investigate how the cell lines respond to efficacious drugs identified by the Desmoid Collaboration for a Cure What effects are different for each desmoid-normal fibrobast pair for all drugs? What effects are the same for each desmoid-normal fibrobast pair for all drugs?
Metabolomics Meets Desmoid Tumors Basic Biology Use broad spectrum and targeted metabolomics to investigate: Primary desmoid tumor cell lines Matched normal fibroblast cell lines Unaffected fibroblast cell line What biochemical processes differentiate the matched desmoid tumors from the adjacent fibroblast? What biochemical differences are there between the matched fibrobasts and the unaffected?
Metabolomics Meets Desmoid Tumors Recurrence and Prediction Biomarkers Use broad spectrum and targeted metabolomics to investigate tissue or cells associated with a primary dissections verse N+1 dissections What metabolites define the primary mass verses the N+1? Can metabolites be found that predict likelihood of regrowth? Use broad spectrum and targeted metabolomics to predict response to treatment Partner with a clinician running a clinical trial Identify patients that are high responders and low responders
1 H NMR Spectrum of Primary Cell Line 233 RTI RCMRC Preliminary Data Glycine Carnitine Glutamate Glutamine Lactate Threonine myo-inositol Alanine Creatine phosphate Lactate Glucose Threonine Creatine Creatinine Methionine N-acetyl amino acids Arginine Lysine BCAA
1 H NMR Spectrum of Primary Cell Line 233 and 235 RTI RCMRC Preliminary Data Media from Primary Cell Line 233 Media from Primary Cell Line 235 Blank Media Lactate Succinate Pyruvate BCAA Glutamate Alanine Propylene Glycol 3-HBA 3-Methyl-2- oxovalerate
Metabolomics and Barth Syndrome Rare disease characterized by dilated cardiomyopathy skeletal myopathy neutropenia short stature Transmitted from mother to son as an X-linked genetic condition as mutation of the tafazzin (TAZ or G4.5) A RTI RCMRC Pilot and Feasibility Study: NMR and LC-MS analysis of plasma Further define metabolic and molecular pathways involved in metabolism Identify potential targets for treatment 23 Barth Syndrome patients and 11 age-matched controls Dr. Hilary Vernon Johns Hopkins U. Dr. Yana Sandlers Cleveland State U.
NMR and LC-MS of plasma from Barth Syndrome Cases and Healthy Subjects NMR NMR Library Matched Bins VIP p-value* 3-Hydroxybutyrate 2.2 0.005 Carnitine, Lipids/Fatty Acids 2.8 0.026 Creatinine, Overlap 1.5 0.001 Lipids/Fatty Acids (4) 1-2.3 0.012-0.062 Methionine 1.8 0.003 Proline, Lipids/Fatty Acids 1.4 0.142 Unsaturated Lipids/Fatty Acids (2) 1.5-1.9 0.078-0.154 VLDLs 4.3 0.023 VLDLs, Unknown 5.1 0.136 LC-MS Biocrates p180 assay Acyclcarnitines, Amino acids, Biogenic amines, and Glycerophospholipids all differentiated the Barth Syndrome patients from the controls. Control- Case-
Metabolomics and Target Identification Distribution of Biochemical Functions
RTI - RCMRC Susan Sumner Center Director Wimal Pathmasiri NMR & GC-MS Tim Fennell In vivo Metabolism Susan McRitchie Data Analysis Zach Acuff Biostatistics Bob Clark Genetics Jocelin Spruill GC-MS Jim Carlson LC- and GC-MS Jessica Gooding LC-MS Andrew Novokhatny Quality Control Tammy Cavallo Quality Control Ninell Mortensen Microbiology Kelly Mercier NMR Jason Burgess NMR Rod Snyder LC-MS Delisha Stewart Cell Biology Keith Levine Metallomics James Harrington Metallomics
Funding NIDDK: NIH Common Fund 1U24DK097193: NIDDK: Sumner, RTI, PI NIH Eastern Regional Comprehensive Metabolomics Resource Core NIEHS U2C ES02654401: Timothy Fennell, PI Children s Health Exposure Analysis Resource (CHEAR) Hub NIGMS: NIH Common Fund 5R25GM103802: Martin Kohlmeier, UNC-CH, PI Online learning platform introducing clinicians and researchers to metabolomics. NEI: NIH Common Fund R01EY012224: Ellen Weiss, UNC-CH, PI Desensitization of Cone Visualization Signaling Pathways. NHLBI: NIH Common Fund HHSN268201300021C:Herb Seltzman, PI; Metabolite Standards Synthesis Core NIDDK: 1UMDK10086601: PI s: William Smoyer, Nationwide Children s Hospital & Larry Greenbaum, Emory. Integrated Proteomics and Metabolomics for Pediatric Glomerular Disease NIEHS: U19ES019525- year 5: PI: Timothy Fennell Estimating Human Health Risks from Exposure to Nanoparticles NCATS: UL1TR00111: PI: John Buse (UNC-CH), North Carolina Translational and Clinical Sciences Institute- NCTraCS