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The Metabolics Of Cancer

Tackling cancer requires a multi-pronged strategy. Currently, many of the cancer drugs on the market work by inhibiting the signaling pathways that activate cell division. These pathways are often the root cause of cancer—a mutated gene leads to a dysfunctional signaling protein which tells the cell to divide inappropriately. In these cases, the cancer may be treated by inhibiting the dysfunctional protein.

Nevertheless, selectively targeting the metabolic changes that cancer cells undergo is one prong worth examining. In this WEEKLY, we’ll look at some of these metabolic approaches, and discover another avenue to target cancer.

TERM OF WEEK: METABOLOME

The metabolome is the complete set of small molecule chemicals found within a biological sample—think a cell, tissue, organ, or organism. These small molecules may be either the broken down products of normal metabolic reactions, or ingested from outside sources (drugs, food additives, etc.). The tumor metabolome is typically different from other tissues within the body, and therefore may be a rich source of drug targets.

Got Some Glutamine?

Cancer cells consume the amino acid glutamine at a much higher rate than healthy cells. This dependence is thought to arise from genetic changes in the cancer cells which alter fundamental metabolic pathways. Preclinical research has shown cancer cells cultivated in low glutamine conditions show a substantially reduced amount of growth—a phenomenon sometimes referred to as “addiction,” implying the cells are dependent on glutamine.

Calithera Biosciences (South San Francisco, CA) is bringing that finding into the clinic with its experimental drug CB-839, which inhibits the enzyme glutaminase, the first step in the cancer cell’s utilization of glutamine. Animal studies suggested CB-839 may show efficacy towards triple negative breast cancer, non-small cell lung cancer, multiple myeloma, and renal cell carcinoma. The company is conducting Phase I trials of CB-839 in both solid and hematological tumors.

Arginine, Anyone?

Immunotherapies—therapies that activate a patient’s immune system to fight cancer—are increasingly popular. They are viewed as a way to effectively fight cancer with fewer side effects than traditional chemotherapies.
T-cells—the “warrior cells” of the immune system—can be very effective partners in immunotherapy. The highly effective checkpoint inhibitor and CAR-T therapies activate cancer-fighting T-cells.

T-cells, like cancer cells, also require specific nutrients to function optimally. T-cells (and other white blood cells) need the amino acid arginine to be fully active. In some tumors, the enzyme arginase (which breaks down arginine) is overactive. Calithera’s other drug candidate, CB-1158, works to inhibit arginase, thereby increasing arginine concentrations and helping to ensure that T-cells are fully active—and can battle with tumor cells. Calithera is preparing to submit an investigational new drug application to begin clinical studies in 2016.

Please Pass The SUGAR

Occasionally, people claim that sugar consumption in and of itself causes cancer. This is simply not true. All cells, including healthy cells, require some sugar (glucose) to live—it’s where they get their energy from. Cancer cells grow and divide more rapidly than other cells in the body, which is why they consume excess glucose once established. But simply removing sugar from the diet will not prevent cancer. Cancer is caused by changes to the DNA of cells which interferes with their ability to regulate cell growth and division. Once a cell has become cancerous, reducing sugar in the diet will not directly stop a tumor.

Too much sugar is unhealthy and may cause obesity—which is linked to increased risks for several types of cancers, as well as heart disease. Excessive sugar consumption is also a factor in developing type 2 diabetes. So, avoiding excess sugar in the form of sweet snacks and processed food is good for your health, but it is not a magic bullet for treating cancer.

Cancer cells do use glucose at a significantly higher rate—as much as 200 times higher—than normal cells. This metabolic abnormality could potentially be exploited as a therapeutic target. Preclinical studies suggest that therapies aimed at blocking cancer cells’ uptake or use of sugar may be therapeutically useful, and researchers are working on ways to translate this into clinical practice.

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