A recent study from Washington University School of Medicine in St. Louis outlines a novel approach to starving tumor cells that is based on a vulnerable point in cancer cell metabolism. The study was published in the January 24 issue of Cell Reports.
Numerous prior studies that explore the concept of blocking nutrients from reaching cancer cells have been unsuccessful, as cancer cells are able to find alternate ways to keep growing.
This approach, which is specific to sarcomas, examines the role of environmental arginine, a protein building block that is vital to the growth of sarcomas. By removing the environmental arginine, cells begin the process of autophagy, or “self-devouring” to survive.
By discovering the weak points in cancer cell metabolism, the backup fuel supply pathways are uncovered, which can then be targeted with drugs that will block them.
A small clinical trial is planned to evaluate this treatment strategy.
Senior author, Brian Van Tine, MD, PhD stated,”Healthy cells don’t have this weakness. We have been trying to create a therapy that takes advantage of the metabolic defect, because in theory, it should target only the tumor. Basically, the defect allows us to force the tumor cells to starve.”
Tumor cells require certain building blocks to survive and grow. A majority of sarcomas have lost their ability to produce their own arginine. Since they cannot produce their own, they seek to obtain arginine from the surrounding environment. Arginine can be obtained from the blood, where it is prolific, and is easily accessible, but by removing this environmental supply the cells are cut off from this vital element.
Van Tine elaborates: “When we use a drug to deplete arginine in the blood, the cancer cells panic because they have lost their fuel supply, so they rewire themselves to try to survive. In this study, we used that rewiring to identify drugs that will block the secondary routes.”
Depletion of arginine does not effect healthy cells, because they do not rely on external sources of arginine.
The arginine-depleting drug is currently in clinical trials for other cancers, but has been ineffective because it activates the alternate pathways that allow the cancer cells to grow. It may, however, become an important metabolic therapy for cancer if used in combination with other drugs that target the alternate pathways.
When cancer cells with this metabolic defect are deprived of environmental arginine, they shift from a system that burns glucose to a system that burns an alternate fuel, glutamine. By adding a glutamine inhibitor to the arginine-depleting drug, it becomes lethal to the cells.
Although the study is specific to sarcomas, this novel approach may have wider applications, as other cancers also have this metabolic defect.
Van Tine and his associates at Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine are planning a clinical trial of the arginine-depleting drug in patients with sarcoma.
Source: Washington University School of Medicine