Double-barreled drug strategy cancels cancer's backup plans
Cancer is a crafty foe. Scientists have long tried to starve out tumors by cutting off their access to nutrients, but cancers can quickly enact backup plans and start getting fuel from other sources. Now, researchers at Washington University's School of Medicine have found a way to deliver a one-two punch to tumors by inhibiting their primary fuel supply and a secondary "salvage pathway" at the same time. The finding could lead to treatments that kill cancer cells without damaging healthy tissue.
The study makes use of a well-known function of cancer's metabolism, particularly common in sarcomas – a form of cancer that arises in fat, muscle, bone, cartilage and other connective tissues. These tumors have a metabolic defect that prevents them from producing the amino acid arginine, vital for cell division, forcing them to source it from the cells around them.
"We have determined that this metabolic defect is present in 90 percent of sarcomas," says Brian Van Tine, senior author of the study. "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."
Left to its own devices, cancer has no trouble pulling the fairly-common arginine out of the bloodstream and fuelling its growth. But when an arginine-inhibiting drug is introduced, the cancer cells have no choice but to turn inwards and consume their internal supply of arginine. The beauty of the technique is that it singles out the sarcoma: since healthy cells produce their own arginine just fine, they remain unaffected by reduced environmental arginine.
Unfortunately, while this process does slow the tumor's growth, it doesn't kill it completely: Eventually, the cancer resorts to a secondary fuel source. But by backing the cancer cells into this corner, the researchers were able to track its backup mechanism, and then develop drugs that target those as well.
Without arginine, the cancer cells begin burning different fuels, like glutamine or serine. By adding drugs that inhibit those amino acids to the original arginine inhibitor, the team found that the cancer cells began to die off. Other studies have found similar success, including work from the Australian National University that used RNA silencing to restrict glutamine, resulting in a 96 percent drop in the cancer cells' growth rate.
"Cancer doesn't die when you halt its primary fuel supply," says Van Tine. "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."
While the technique is most effective in sarcomas, the researchers say it could be applied to other types of cancer that have the same metabolic defect, including some breast, colon, lung, brain and bone tumors. While the arginine-inhibitor is already undergoing clinical trials, it hasn't proven itself very effective yet – but, the researchers point out, that's likely because it doesn't stop cancer growth unless it's paired with other drugs that target cancer's Plan B. With that in mind, the team is hoping to start their own clinical trials.
"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," says Van Tine. "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."
According to the team, all of the drugs used in the study have already been approved by the US FDA, with some already in use in clinical trials.
The research was published in the journal Cell Reports.