Clinical Metabolomics: Analytical Tool for Drug Development. Vladimir Tolstikov 1, * 1 Director of Metabolomics, BERG LLC, Framingham, MA 01701, U.S.A. * Corresponding author: vladimir.tolstikov@berghealth.com 1
Clinical Metabolomics: Analytical Tool for Drug Development. 2
Abstract: It is recognized that altered metabolic states reports on the chronic and acute disease statuses. Decades of research have shown that metabolism is not a self- regulating network operating independently but rather heavily integrated into every cellular process and involved in organ system functions. Therefore global monitoring of metabolic processes is recommended for more comprehensive understanding of the initiation and advancement of disease. Mass spectrometry based metabolomics, in particular, demonstrates tremendous promise in delivering high throughput quantitative information on alterations in metabolism associated with disease onset/progression and response to pharmaceutical intervention. Recent advances in mass spectrometry and informatics tools have facilitated emerging in house OMICS platforms capable of translating biological output into viable therapeutic candidates and assist in stratifying patient populations. At BERG, we have implemented an industrial level high throughput metabolomics platform providing both high quality and depth of information allowing for reliable and broadest capture of the metabolome for the pre-clinical and clinical matrixes analyzed. Global metabolomics platform dedicated for theranostic and clinical studies as well as tracer metabolomics are harvested to facilitate CDx biomarkers discovery in a unique way. Highlights of the BERG’s in -depth patient stratification approaches as well as biology based drugs are presented. Keywords: Metabolomics, discovery, clinical, network, patient stratification, CDx markers. 3
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Szymanska E., Saccenti E., Smilde A. and Westerhuis J. (2012). Metabolomics, 8: 3-16 N samples P variables ….. It is becoming increasingly evident that many biological studies are underpowered with regard to their ability to come to a robust and statistically significant and justifiable biological conclusion .…. 6 8
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Robert Powers: The Current State of Drug Discovery and a Potential Role for NMR Metabolomics, J. Med. Chem. , 2014, 57 (14), pp 5860 – 5870 14 14 14
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Case summary 1. A ketogenic diet dramatically increases and sustains endogenous FGF21 production in wild- type and PPARα KO mice indicating PPARα -independent regulation of FGF21. 2. A cluster of metabolites associated with FGF21 production in PPARα KO mice was identified and suggests this increase is associated with increased metabolic stress in the liver. 3. Pattern correlation and two way ANOVA analyses suggest significant changes to the transmethylation pathway and glutathione metabolism in response to acute dietary challenges. 22 22 22
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