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14 | APRIL 15, 2017 | GENengnews.com | Genetic Engineering & Biotechnology News A vast body of literature on the metabolic pathways and biochemical reactions has been generated from research done over many decades. Mining this literature is one method to deduce potential metabolic targets for new cancer therapies. Another approach is to metabolically screen cells before and after treatment, or to analyze cancer cell metabolism and compare it to the metabolism of normal cells. "Cancer cells require lots of energy to grow and prolif- erate, and many pathways get co-opted into providing for these bioenergetic and biosynthetic needs," says John Ryals, Ph.D., president and CEO of Metabolon. Advances in mass spectroscopy techniques and data analysis greatly improve the ease of obtaining metabolic data from cells. "We need only about 10–25 mg of a cell pellet to determine the meta- bolic profile of the cells," continues Dr. Ryals. In addition to studying cancer, Metabolon investigates many other metabolic diseases. Recently, company repre- sentatives contributed to a study demonstrating that me- tabolomics could be an effective tool in precision medicine for disease risk assessment and customized drug therapy in clinics. This study, which appeared in the Proceedings of the National Academy of Sciences, identified metabolic abnor- malities consistent with early indications of diabetes, liver dysfunction, and disruption of gut microbiome homeostasis. "On a certain level, all diseases are metabolic," comments Dr. Ryals. "They are a physical manifestation of what is go- ing on with a patient. Looking for functions of genes (for which the function was previously unknown), we collabo- rated with companies such as Human Longevity, bringing together genomic and metabolic data, to find the function of these genes. "These initial studies have analyzed the genomes and me- tabolomes of 2,000 to 3,000 people, and from those large sets of data, we've been able to discover the function of about 200 to 300 genes. With this new knowledge, we look forward to a day when there is enough genomic and metabo- lomic information on much larger numbers of people to give us an even clearer picture of how this all fits together. Some day, we will be able to understand the function of all genes and where their metabolic outcomes lead." Opting for Strategic Interventions Drug candidates that function by modulating metabolism do not have to be identified through complex screens of the metabolome. If the literature is reviewed with an eye toward finding reactions that are essential for metabolic processes, ideas can be generated for drugs that work via novel mecha- nisms of action to impinge on metabolic reactions. The latter approach—reviewing pathway knowledge to develop mechanistic insights and identify strategic opportu- nities—was followed by Paul Bingham, Ph.D., vice president of research at Cornerstone Pharmaceuticals and professor of biochemistry and cell biology at Stony Brook University. Mechanistic insights helped Dr. Bingham and colleagues de- velop a first-in-class drug that attacks core mitochondrial metabolism in tumor cells. "We were able to tap into the vast knowledge base of metabolism to observe where regulatory processes are recon- figured in tumor mitochondria, inviting cancer-specific tar- geting," recalls Dr. Bingham. "These observations suggested that a lipoate analog can directly address lipoate-dependent, tumor-specific regulatory targets, resulting in efficient, selec- tive tumor cell death. A lipoate-containing enzyme, pyruvate dehydrogenase (PDH), is central to metabolism in the mitochondria of can- cer cells. Exploiting this bit of knowledge, Dr. Bingham's team worked to develop a nonreductive, noncatalytic analog of PDH lipoate, CPI-613. The investigators reasoned that CPI-613 had the potential to attack kinase control of PDH activity, and to do so selectively in tumor cells. When CPI-613 was evaluated in cell cultures, cells derived from cancer tumors were seen to die when the drug was pres- ent at 100 µM. Normal, noncancerous cells remained viable. Moreover, tumor cells in the more hostile in vivo solid tumor environment are even more sensitive to CPI-613. "Metabolism in cancer cells is different from normal cells," notes Dr. Bingham. "The changes are predictable. They tend to converge on several metabolic properties. Metabolic drugs (or drugs with a metabolic mechanism of action) can be used to develop cancer therapies effective in many patients, not just small subgroups. "Many new cancer drugs only target cancers that carry a specific mutation. Metabolic drugs target a metabolic pro- cess common to many or all cancers. Hopefully, these new therapies can be used on a broader range of cancers." Disrupting One-Carbon Metabolism Bringing together the power of genetic and metabolic fields, Gregory Ducker, Ph.D., postdoctoral research fellow in the Rabinowitz Laboratory at Princeton University has found a new way to disrupt one-carbon metabolism. In a nutshell, one-carbon metabolism refers to reactions that move single carbon groups around cellular metabolic pathways. "One-carbon metabolism plays a big role in the produc- tion and methylation of DNA," explains Dr. Ducker. "Hav- ing too much DNA methylation due to an overabundance of one-carbon metabolism is bad for the cell. It can cause hy- permethylation (and thus inactivation) of tumor-suppressor genes. We started investigating one-carbon metabolism with a question: Can cancer genetics lead us to new druggable genes in the one-carbon pathway? "During initial literature searches, we focused on mito- chondrial genes that process serine into one-carbon units, be- cause they have been recently shown to be highly upregulat- ed in cancer. We began by targeting the most overexpressed metabolic enzyme in cancer, MTHFD2." This enzyme, which processes one-carbon units in the mitochondria, has been cited in several studies as a poten- tial drug target. However, when MTHFD2 gene knock- down was evaluated in cell culture and xenograft models, the results were disappointing. A treatment targeting just this enzyme, it appeared, would not be so effective as to warrant development. "Most likely, the lack of efficacy was due to cells compen- sating for the loss of mitochondrial MTHFD2 through acti- vation of the cytosolic one-carbon pathway via SHMT1," Dr. Ducker suggests. "Knocking out both of these enzymes, OMICS Feature See Metabolic Quirks on page 16 Finding Targets in Cancer's Metabolic Quirks Continued from page 1 Researchers at Stony Brook University, in the lab of Paul Bingham, Ph.D., found a lipoate analog that can selectively induce inhibition of pyruvate dehydrogenase and α-ketoglutarate dehydrogenase, mitochondrial enzymes involved in cancer cell metabolism in vitro. The compound, CPI-613, is now being developed by Cornerstone Pharmaceuticals. Top row: Cells treated with 100 µM CPI-613. (Cell lines derived from cancer tumors undergo cell death, while cell lines derived from normal tissue remain viable.) Bottom row: The same cells treated with vehicle only.