2016 Archived Content
This day-and-a-half conference emphasizes presentations that analyze metabolomics data in a larger context of cellular functioning or disease states. Metabolomics provides a chemical snapshot of a cell in terms of molecular components (metabolites) of specific cellular processes. It’s a way to compare cells under different conditions such as healthy v. diseased or drug-treated versus non-treated. Our conference starts with a few introductory presentations about the major technologies in the field. Then the focus will shift to examples of metabolomics uncovering potential new drug targets or explaining the effectiveness of particular therapeutic strategies. Case-studies will be mostly from cancer metabolism and cardiometabolic disease areas.
Final Agenda
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Wednesday, September 21
11:20 am Conference Registration Open
11:25 Enjoy Lunch on Your Own
2:40 Refreshment Break in the Exhibit Hall with Poster Viewing
3:20 Chairperson’s Opening Remarks
Edward Driggers, CSO, General Metabolics
3:35 Understanding Disease Mechanisms through LC/MS-Based Metabolomics
Elizaveta Freinkman, Ph.D., Research Scientist and Manager, Metabolite Profiling Facility, Whitehead Institute, MIT
Liquid chromatography–mass spectrometry (LC/MS) is the most versatile analytical technique for metabolomics. Drawing on the past several years of research at the Whitehead Institute Metabolite Profiling Core Facility, this presentation will provide an overview of current LC/MS technologies. Sample preparation, method development, data analysis, and quality control will be discussed in the context of specific metabolomic experiments and the biological insights that they enabled.
4:05 Translating Inhibitors of Mutant IDH into the Clinic for Myeloid Malignancies
Eytan M. Stein, M.D., Assistant Attending Physician, Department of Medicine, Memorial Sloan Kettering Cancer Center
Mutations in the conserved enzymatic active sites of Isocitrate Dehydrogenase isoforms 1 and 2 (IDH1 and IDH2) lead to novel enzymatic activity that catalyzes the conversion of α-ketoglutarate to β-hydroxyglutarate (2-HG) and a block in cellular differentiation. Inhibitors of mutant IDH, both alone and in combination with standard-of-care therapy are in early and advanced clinical studies and show remarkable efficacy.
4:35 Using Metabolomics to Discern New Target Opportunities from Established Models
Kirk Beebe, Ph.D., Director, Application Science, Metabolon
Although ‘omic technologies have matured to the point that targets can potentially be mined directly from human cohorts, model systems continue and will remain an important avenue for probing disease mechanisms and efficacy of novel molecules. Through providing a functional assessment of the phenotype, we will discuss how metabolomics offers a mechanism to more fully interrogate the functional traits of model systems to identify new target opportunities.
5:05 Refreshment Break in the Exhibit Hall with Poster Viewing
5:40 Separating Metabolites Based on Their Structural Properties – A Case Study in Central Carbon Metabolome and a Path to Metabolite Molecular Structure Digitization
Gang Xing, Ph.D., Principal Scientist, CVMET Department, Pfizer Biomedical Institute
Cellular metabolites consist of vastly diverse chemical structures that can be described by structural templates and functional groups. A mixed mode LC strategy was developed to separate central carbon metabolites basing on their molecular structure properties, with a prediction algorithm for extension to other molecular families. Integrated with HRAM-QExactive plus Mass Spectrometry, stable isotope labeling and modeling, its application to derive biological insight will be shown.
6:10 Application of Stable Isotope Labels and Flux Analysis in Drug Discovery
Thomas Roddy, Ph.D., Senior Director, Cellular Metabolism, Agios Pharmaceuticals, Inc.
6:40 End of Day
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Thursday, September 22
7:30 am Registration Open and Morning Coffee
8:30 Chairperson’s Remarks
Peter Juhasz, Ph.D., Director, Mechanisms and Pathways, Biogen
8:45 KEYNOTE PRESENTATION: IDENTIFYING INDICATORS OF DISEASE AND DRUG ACTIVITY USING METABOLOMICS
Clary B. Clish, Ph.D., Director, Metabolite Profiling, Broad Institute of MIT and Harvard
Metabolomics is powerful tool to study metabolic perturbations associated with both disease and drug activity. The presentation will highlight recent efforts to identify a plasma metabolic signature of pancreatic cancer in human cohorts years before clinical diagnosis of disease as well as an example of an effort to elucidate the molecular mechanism of action of the MS therapeutic dimethylfumarate.
9:15 Identifying Inhibitors of Oncology Target, Phosphoglycerate Dehydrogenase, with Metabolite Profiling
Michael Pacold, Ph.D., Postdoctoral Research Fellow, Sabitini Lab, MIT
In the canonical glucose-derived serine synthesis pathway, Homo sapiensphosphoglycerate dehydrogenase (PHGDH) catalyzes the first, rate-limiting step. Genetic loss of PHGDH is toxic towards PHGDH-overexpressing breast cancer cell lines even in the presence of exogenous serine. We have used a quantitative high-throughput screen to identify small molecule PHGDH inhibitors, and validated these compounds using metabolite profiling. I will discuss the role of metabolomics in validating these compounds.
9:45 Metabolomic Analysis and CardioMetabolic Drug Development
Stephen F. Previs, Ph.D., Senior Scientist, Translational Biomarker - CardioMetabolic Disease, Merck & Co.
The presentation will consider the combined use of isotopic flux data and concentration profiling to elucidate if and how one has modulated carbon-energy flow. We will also consider the impact of sub-cellular compartmentation and metabolic heterogeneity on the data interpretation.
10:15 Coffee Break in the Exhibit Hall with Poster Viewing and Poster Competition Winner Announced
11:10 Genetic and Metabolomic Dissection of One-Carbon Metabolism
Gregory Ducker, Ph.D., Postdoctoral Research Fellow, Rabinowitz Laboratory, Princeton University
One-carbon metabolism is the most consistently upregulated metabolic pathway in cancer. Integrating genetic and metabolomic methods, we investigated the compartment specific roles for this metabolism in cancer initiation and proliferation. In most cancers, 1C units are produced in the mitochondria together with glycine, NADPH and NADH. Loss of the mitochondrial pathway, slows, but does not inhibit tumor growth, which is now supported by the cytosolic pathway.
11:40 Panel Discussion: Challenges in Metabolomic Applications
Moderator:
Peter Juhasz, Ph.D., Director, Mechanisms and Pathways, Biogen
Panelists:
Clary B. Clish, Ph.D., Director, Metabolite Profiling, Broad Institute of MIT and Harvard
Elizaveta Freinkman, Ph.D., Research Scientist and Manager, Metabolite Profiling Facility, Whitehead Institute, MIT
Stephen F. Previs, Ph.D., Senior Scientist, Translational Biomarker - CardioMetabolic Disease, Merck & Co.
Thomas Roddy, Ph.D., Senior Director, Cellular Metabolism, Agios Pharmaceuticals, Inc.
- Metabolic profiling -- targeted or untargeted?
- Software tools and strategies for untargeted data processing
- Pathway analysis: making sense of metabolic profiling
- Analyzing polar metabolites
- Questions from audience
12:10 pm Luncheon Presentation: Atlas of the Human Metabolome "A New Avenue for Target Discovery and Validation"
John Ryals, Ph.D., President and CEO, Metabolon
Metabolomics has evolved to accompany tools like genomics in the quest to unlock human health and disease. The ability to collect so much data directly on human subjects offers the potential to deliver new targets that will have unequivocal relevance to human disease. By producing a comprehensive read-out of a living system’s metabolic profile, we will discuss how metabolomics is creating an “atlas” by which new targets
1:30 Refreshment Break in the Exhibit Hall with Poster Viewing
2:15 Chairperson’s Remarks
Raju Pusapati, Ph.D., Scientist, Ribon Therapeutics; formerly Postdoctoral Research Fellow, Discovery Oncology, Genentech
2:20 Targeting Glycolysis in Cancer: Opportunities and Challenges
Raju Pusapati, Ph.D., Scientist, Ribon Therapeutics; formerly Postdoctoral Research Fellow, Discovery Oncology, Genentech
Although glycolysis is substantially elevated in many tumors, therapeutic targeting of glycolysis in cancer patients has not yet been successful, potentially reflecting the metabolic plasticity of tumor cells. Employing metabolomics approaches, we identified the nature of the metabolic plasticity in cancer cells that promote escape from glycolytic dependency. These findings reveal novel combinatorial therapeutic strategies to realize the potential benefit from targeting the Warburg effect.
2:50 Hyperpolarized Metabolic MRI in Drug Discovery and Development
John Kurhanewicz, Ph.D., Professor, Pharmaceutical Chemistry, University of California San Francisco
The characteristic features of tumor metabolism have provided opportunities to detect and grade disease and in measuring therapeutic response using metabolic imaging techniques. This lecture will focus on imaging tumor metabolism before and after therapy using hyperpolarized 13C-labeled cell substrates, in which hyperpolarization of the 13C nucleus increases its sensitivity by more than 5-orders of magnitude, and the translation of this technique into the clinic.
3:20 Session Break
3:30 The First Small Molecule Inhibitors and Co-Crystal Structures of PHGDH
Scott Cowen, Ph.D., Discovery Sciences, AstraZeneca R&D Boston
The conversion of 3-phosphohydroxyglycerate to 3-phosphohydroxypyruvate catalyzed by 3-phosphohydroxyglycerate dehydrogenase (PHGDH) is the first and rate-limiting step in serine biosynthesis in humans. A number of studies have implicated PHGDH in tumorigenesis and tumor proliferation. Using a dual fragment and HTS based screening approach, we were able to generate what we believe to be the first potent series of small molecule inhibitors of PHGDH.
4:00 Targeting Amino Acid Metabolism for Cancer Treatment
Ethan Emberley, Ph.D., Scientist II, Biology, Calithera Biosciences
CB-839 is an orally-bioavailable glutaminase inhibitor that blocks the ability of tumors to use glutamine as a nutrient source. CB-839 has antitumor activity in a number of tumor models by reducing levels of key metabolites including TCA cycle intermediates, glutathione and nucleotides. Genomic, proteomic and metabolomics analysis has identified biomarkers and combination partners for CB-839 that are under investigation in ongoing Phase 1 clinical studies.
4:30 A Novel Oncology Candidate Selectively Attacks Cancer Mitochondrial Metabolism
Paul M. Bingham, Ph.D., Vice President, Research, Cornerstone Pharmaceuticals and Professor, Biochemistry and Cell Biology, Stony Brook University
CPI-613, a non-redox active lipoate analog, represents a first-in-class group of drugs attacking core mitochondrial metabolism selectively in tumor cells. This drug is producing striking clinical results in several cancers, including AML and PDAC. CPI-613’s unprecedented MOA also renders it a powerful probe of the details of cancer metabolism, revealing clinically relevant features of the altered anabolism and catabolism in tumor cells.
5:00 Close of Conference
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