Clinical OMICS

MAY-JUN 2019

Healthcare magazine for research scientists, labs, pathologists, hospitals, cancer centers, physicians and biopharma companies providing news articles, expert interviews and videos about molecular diagnostics in precision medicine

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Page 20 of 50 May/June 2019 Clinical OMICs 19 of non-oxygen driven metabolism. If the mechanistic ori- gins of altered metabolism in cancer can be understood, alleviating the growth and progression of tumors as well as discovering therapeutic strategies could be possible. Also, drug metabolism could lead to improvements in the metab- olism of that particular drug and combinatorial therapy. In order to understand metabolomics in cancer, Subrama- niam explained, we have to start at the Warberg effect. The Warberg effect describes that cancer cells favor glycolysis rather than the oxidative phosphorylation—the ATP pro- duction method utilized by the other cells in the body. This discovery, described in 1927 in the Journal of General Physi- ology for which Otto Warberg was awarded the Nobel Prize in 1931, has been a topic of discussion for decades, accord- ing to Subramamiam. And, the research surrounding this metabolic phenome- non has increased in the last twenty years as people have started to question the altered metabolism illus- trated by cancer cells. Now, almost a century later, the field is moving with break- neck speed. Oliver Fiehn, Ph.D., professor at the University of California, Davis, and director of the West Coast Metabolomics Center, noted that "it is great that metabolism is recognized as a hallmark of cancer and that researchers and clinicians embrace this idea from finding cures to other interventions." The poster child The promise held by metabolomics to advance cancer treat- ment is perhaps best illustrated by the seminal 2009 Nature paper illustrating a causal association between genetics, metabolism, and cancer. The collaborative paper, "Can- cer-associated IDH1 mutations produce 2-hydroxygluta- rate" showed that mutations in the isocitrate dehydrogenase 1 (IDH1) gene lead to production of an oncometabolite, 2-hydroxyglutarate (2HG). The excessive 2HG accumulates, contributing to the formation and malignant progression of gliomas. Many of the authors on the landmark paper were from Agios Pharmaceuticals, a company that has turned this metabolomic discovery into a druggable target. With two drugs having been granted FDA approval, TIBSOVO (Ivosidenib) and IDHIFA (Enasidenib), Agios is successfully bringing metabolomics and cancer from the bench to bedside. IDHIFA was FDA approved in August, 2017 for patients with relapsed or refractory acute myeloid leukemia (AML) who have IDH2 mutations and TIBSOVO was granted FDA approval in July 2018 for patients with relapsed or refractory acute myeloid leukemia with an IDH1 genetic mutation. Metabolomics was the key to finding how the genomic alteration changed the cancer, noted Andreas Huhmer, Ph.D., senior director, proteomics and metabolomics at Thermo Fisher Scientific. He adds that because metab- olomics is "very actionable" it allows the study of how organisms react to change which is more difficult to study using only genomics. Building the foundation A disease state recognized by deviations from the healthy state can only be recognized when the normal profile is established. "It is only then that deviations become mean- ingful," noted Subramaniam. Therefore, baselines must be established—perhaps the creation of a Human Reference Metabolome, of sorts. But, it takes a lot more to organize a metabolomic data- base than a genomic one. "There are 23,000 genes, but there could be millions of metabolites" noted Teresa Fan, Ph.D., professor at the University of Kentucky Markey Cancer Center. Although a refer- ence metabalome may not be possible due to its vast complexity, building large databases of metabolomes is work that is at the heart of metabolomics today. Nightingale Health in Hel- sinki, Finland and UK Bio- bank announced plans in the summer of 2018 to ana- lyze metabolic biomarkers in 500,000 blood samples. The work, which is funded by Nightingale and uses its biomarker profiling technology, will be incorporated into UK Biobank's public database— after a nine-month period during which Nightingale has exclusive access. Subramaniam heads up an NIH-funded project known as the Metabolomics Workbench—creating a public, inter- active repository for metabolomics metadata and exper- (continued on next page) Oliver Fiehn, Ph.D., director, West Coast Metabolomics Center Andreas Huhmer, Ph.D., senior director, Thermo Fisher Scientific.

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