Finding Chinks in the Armor: Cancer’s Need for Metabolites

Illustration of energy metablism in cell.Cancer has been studied for decades by scientists trying to find a vulnerability to exploit and testing compounds to develop as potential drugs. As the “Emperor of All Maladies”, cancer has proven itself to be a wily beast with many varieties of genetic mutations for eluding cellular control, tireless in its ability to divide and spread. In the end, a cancer cell is still a cell and subject to its environment even though cancer does not play by the same rules as the normal cells that exist around it. To be able to grow, a cell needs access to metabolites, molecules needed for building the materials and machinery needed by the cell to function and divide. These requirements also offer potential pathways to target for halting cancer growth and spread.

All cells use glucose to generate ATP, but normal and cancer cells differ in how glucose is converted to ATP. Most cells use glucose in oxidative phosphorylation, but cancer cells use aerobic glycolysis, converting glucose to lactate without oxygen. This Warburg effect (glucose converted to lactate) is a hallmark of cancer cells as they take up glucose at a much higher rate than normal cells. Blocking glucose uptake is one way to target cancer cells. While 2-deoxyglucose (2DG) has been shown to slow glucose uptake in vitro, the compound proved toxic in clinical trials and lower dosages do not seem to be an effective treatment against cancer. While not an ideal drug target, glucose uptake has been helpful in monitoring cancer response to therapies via fluorodeoxyglucose positron emission tomography (FDG-PET).

Despite cancer cells using the Warburg effect, inhibiting oxidative phosphorylation blocks both tumor initiation and proliferation. With cellular respiration such an integral function of cells, targeting might seem like a recipe for toxicity. However, metformin, a type 2 diabetes drug that inhibits the mitochondrial complex I, a part of the respiration chain, has shown antitumor benefits. Not only does cellular respiration produce ATP but it also regenerates oxidized nicotinamide adenine dinucleotide (NAD+) from NADH. The intracellular level of NAD+ needs to be maintained for many cellular processes such as protein deacetylation and oxidation of amino acids and nucleotides. High levels of NAD+/NADH are required by many proliferating cells but lower ratios favor ATP production in the mitochondria, thus manipulating the amount of NAD+ available could inhibit cancer proliferation. Targeting nicotinamide phophoribosyltransferase (NAMPT), a rate-limiting enzyme in a nicotinamide salvage pathway that is a major source of NAD+, has shown some antitumor effectiveness in models, but as a single therapy is not clinically beneficial. Pairing NAMPT inhibitors with other NAD+-depleting drugs may prove more useful, but this combination needs further testing.

Glucose is not the only metabolite consumed at a higher level in cancer cells. The amino acid glutamine is required by dividing cancer cells both as a precursor to amino acids and nucleotides, but also for glutaminolysis that funnels intermediates to the citric acid (TCA) cycle. Glutamine metabolism is so important to some oncogenic signaling pathways that cancers, for example those transformed by MYC, become dependent on glutamine and die without it. Unfortunately, work on glutamine analogs are not effective or toxic when used in human trials. Current research is pursuing inhibitors of glutaminase, an enzyme that converts glutamine to glutamate. Glutaminase inhibitors show decrease proliferation of cancer cells in vitro and in vivo with pending clinical trials for one GLS inhibitor.

Cancer bends cellular machinery to its will by altering the pathways through which a particular molecule is made. Some types of cancer show increased expression of the enzymes involved in serine synthesis. For example, when phosphoglycerate dehydrogenase (PHGDH) is upregulated or duplicated, more serine is produced from a glycolysis intermediary. When small molecules target PHGDH expression, in vitro proliferation of tumor cells are inhibited. However, serine synthesis plays an important role in the central nervous system, blunting some of its value as a cancer treatment. Serine is also taken up from plasma, so another potential way to inhibit cancer is by restricting access to serine. In xenograft models, serine deprivation does slow cancer growth, but this response depends on the mutation and tissue context.

Not all cancers consume more metabolites or overexpress metabolic enzymes. As a consequence of deleting tumor suppressor genes, nearby genes involved in metabolism are also lost. One such metabolic enzyme lost with a tumor suppressor is methylthioadenosine phosphorylase (MTAP), a member the methionine salvage pathway that produces adenosine, which is eventually converted to methionine and AMP. Cells without MTAP are more dependent on de novo purine synthesis. Treating cells with an adenosine analog and the MTAP substrate methylthioadenosine (MTA) is lethal MTAP-deficient cells. Accumulating MTA also inhibits arginine methyltransferase 5 (PRMT5), making MATP-null cells more vulnerable to PRMT5 depletion. However, PRMT5 inhibitors have to compete for binding with MTA and may not be clinically effective.

With cancer cells so driven to divide, they also have increased levels of reactive metabolites. Accumulating reactive oxygen species (ROS) is toxic so tumors need to keep detoxification pathways intact to prevent reactive metabolite buildup. Thus targeting these pathways offer a way to preferentially target cancer cells over normal cells. Targeting antioxidants such as glutathione is another way to exploit the need for cancer to moderate the levels of reactive metabolites in the cell. In fact, targeting glutathione synthesis has inhibited cell proliferation while reducing the amount of intracellular glutathione has resulted in cancer cell death. Alternatively, limiting cysteine availability also depletes glutathione because this amino acid is required for glutathione synthesis. A potential cancer treatment using this method is being tested in clinical trials.

Metabolism plays a key role in cancer initiation and progression so finding the right approach to exploit the full potential of these identified enzymes and pathways will likely prove useful. While these examples of increased need for metabolites or deleting metabolic enzymes suggest cancer vulnerabilities, individually these targets may have little effectiveness or be toxic in clinical settings despite promising research that show benefits in vitro. Inhibiting metabolic enzymes or depleting cells of metabolites also may require a better understanding of the timing when a particular treatment may be most useful. Every identified metabolite is an opportunity to find the right drug for the right cancer at the right time or with the right treatment partner to make it effective.

Looking for ways to interrogate a compound’s potential effect on cancer metabolites? Our portfolio of sensitive assays can measure glucose uptake, nucleotide cofactors, metabolites and oxidative stress.

Reference
Luengo, A., Gui, D.Y., and Vander Heiden, M.G. (2017) Targeting metabolism for cancer therapy. Cell Chem. Bio. 24, 1161–80.

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Sara Klink

Technical Writer at Promega Corporation
Sara is a native Wisconsinite who grew up on a fifth-generation dairy farm and decided she wanted to be a scientist at age 12. She was educated at the University of Wisconsin—Parkside, where she earned a B.S. in Biology and a Master’s degree in Molecular Biology before earning her second Master’s degree in Oncology at the University of Wisconsin—Madison. She has worked for Promega Corporation for more than 15 years, first as a Technical Services Scientist, currently as a Technical Writer. Sara enjoys talking about her flock of entertaining chickens and tries not to be too ambitious when planning her spring garden.

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