Starving Cancer Cells May Lead to Less Toxic Treatments

A recent study found a novel way to inhibit cancer cell metabolism by essentially starving them to death, which may lead to more effective, less toxic treatments.

Inhibiting nutrients from reaching cancer cells and starving them has been a popular target for researchers in the past. However, these methods have not resulted in effective treatments, since cancer cells are known to be resilient, and continuously create new pathways to obtain nutrients.

The authors of the new study discovered a weak point in cancer cell metabolism. By exploiting that weak point, the cells revealed an alternative fuel supply route, according to the study, which was published by Cell Reports. The researchers were also able to identify drugs that can successfully block those secondary routes.

In the study, the authors examined human cancer cells and mice models of human tumors to assess whether inhibiting the weak point and a secondary route would effectively cause cell death. This treatment option shows the promise to treat numerous difficult cancers.

This weak point is common in multiple cancers, including sarcomas, which are cancers of fat, muscle, bone, cartilage, and connective tissue. Sarcomas are typically treated with surgery, radiation, and chemotherapy, but these methods are largely ineffective.

"We have determined that this metabolic defect is present in 90 percent of sarcomas," said senior author Brian A. Van Tine, MD, PhD. "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."

Cancer cells must have basic materials to grow and proliferate, but a majority of sarcomas are unable to manufacture arginine, a protein that is required for cell reproduction, according to the study. Without the necessary mechanisms to create arginine, the cells must obtain the protein from the surrounding areas.

Since arginine is present in the blood, the cancer cells are able to harvest abundant quantities. If this crucial protein is removed, then the cells are unable to grow.

"When we use a drug to deplete arginine in the blood, the cancer cells panic because they've lost their fuel supply," Dr Van Tine said. "So they rewire themselves to try to survive. In this study, we used that rewiring to identify drugs that block the secondary routes."

This proposed treatment would not affect healthy cells in the body since they do not rely on external sources of the protein, and would be less toxic compared with traditional methods. The cells will continue to manufacture their own arginine, and will not be effected by induced starvation from depleting the blood of that protein, according to the study.

Without external sources of the protein, cancer cells then metabolize their internal reservoir. In sarcomas, this slows cancer growth, but does not kill the cells since they are constantly looking for a way to bypass this.

"Cancer doesn't die when you halt its primary fuel supply," Dr Van Tine said. "Instead, it turns on all these salvage pathways. In this paper, we identified the salvage pathways. Then we showed that when you drug them, too, you kill cells. Our study showed that tumors actually shrink under these conditions. This is the first time tumors have been shown to shrink using just metabolism drugs and no other anti-cancer strategies."

Currently, there is an arginine-depleting drug that is being evaluated in clinical trials for liver, lung, pancreatic, breast, and other cancers. Thus far, it has not been effective likely due to cancer cells creating salvage pathways that allow the cells to live.

Despite not showing efficacy, the researchers believe that this drug may create a vital treatment for cancer when used in combination with other drugs that target the salvage pathways.

When environmental arginine is removed, the cells are forced to burn glutamine instead of glucose. The investigators showed that adding a glutamine inhibitor to the arginine-depleting drug can kill cancer cells.

Additionally, depleting arginine can cause the cells to use serine as fuel, so a serine inhibitor would also result in cancer cell death, according to the study.

The authors believe that this method could be used in other types of cancers, such as breast, colon, lung, brain, and bone cancers, where this metabolic defect is also present. The investigators are now planning to conduct a clinical trial of arginine-depleting drugs in patients with sarcomas, according to the study.

"We will start with a baseline trial testing the arginine-depleting drug against sarcomas with this defect, and then we can begin layering additional drugs on top of that therapy," Dr Van Tine said. "Unlike breast cancer, for example, sarcomas currently have no targeted therapies. If this strategy is effective, it could transform the treatment of 90 percent of sarcoma tumors."