Copper-Lowering Drug Stabilizes Advanced Cancer: Research on Wilson's Disease Led to Discovery

By depriving cancer tumors of the copper supply they need to form new blood vessels, researchers in the U-M Medical School have stopped the growth of the disease in a small group of patients with advanced cancer.

Five of six patients whose copper levels were kept at one-fifth of normal for more than 90 days had no growth of existing tumors or formation of new ones, according to a paper published in the January, 2000, issue of Clinical Cancer Research. The sixth patient had progression of only one tumor; all other tumors within her body remained stable. Twelve other patients did not achieve the target copper level, or could not stay at the target level for 90 days, because of disease progression.

The finding is the first evidence in humans that physicians might fight multiple types of cancer by targeting copper as a 'common denominator' of angiogenesis — the process by which tumors grow the blood vessels that allow them to expand beyond a tiny cluster of cells. The copper strategy is not limited to a single type of cancer, as are other anti-angiogenesis agents now being studied.

Sofia Merajver and George Brewer

Patients in the phase I trial at the U-M had metastatic cancer of the breast, kidney, colon, lung, skin, pancreas, prostate, throat, cartilage, blood vessels or endothelium. All had exhausted other conventional treatment options.

The U-M trial used oral doses of an inexpensive compound called tetrathiomolybdate, or TM, to lower patients' copper levels. TM was originally developed for clinical use by George J. Brewer, M.D., Morton and Henrietta Sellner Professor of Human Genetics, to treat people with Wilson's disease, a rare genetic disorder associated with excess copper. His work has shown TM to be the world's most potent anti-copper agent, and safe to use.

Aware of earlier research indicating that copper is important for angiogenesis, Brewer did work in the early 1990s on animal cancer models treated with TM, with encouraging results. Then he teamed up with Sofia Merajver, M.D., Ph.D., associate professor of internal medicine, molecular genetics researcher, and oncologist in the Comprehensive Cancer Center.

Independently, Merajver was interested in exploring the inhibition of angiogenesis at very early stages in cancer development. Together with Brewer, she designed specific animal studies that allowed the team to test whether TM had the ability to prevent tumors from arising in animals at high risk for cancer. Her laboratory has also begun to uncover the molecular and cellular events involved in the inhibition of blood vessel growth by copper deficiency.

Their first results with humans actually came from a trial that was designed only to see how well TM could reduce copper levels in cancer patients, not to test its effect on the cancer itself. At all three daily dose levels given in the trial, copper levels were reduced to 20 percent of normal in four to six weeks. Neither the drug, nor the long-term copper deficiency, produced side effects.

"What began as a scientific hunch now appears to have potential as a simple but effective general anti-angiogenesis strategy," says Brewer. "We are proceeding with a clinical trial aimed at accelerating TM-induced copper reduction and assessing its effect on advanced-stage cancer. Later this year, we hope to test this approach in 100 patients with five types of less advanced cancer." Neither trial is currently accepting patients.

Adds Merajver, "These initial results suggest that the tactic of preventing angiogenesis through copper deficiency holds significant promise. Through this and other therapies, we may one day be able to turn cancer into a chronic or controllable disease or to contribute to its eradication. Still, much more research is needed before we can know the full potential of anti-angiogenesis."

The chemicals pictured above are copper (blue) and several of the tetrathiomolybdate compounds currently under study.

Angiogenesis happens in the body all the time, whether to repair a wound or help with the normal growth of children's bodies. It occurs through a so-called angiogenesis "cascade" — a series of biochemical steps by which cells make and secrete molecules that initiate the growth of capillaries. After the job is done, other molecular "factors" turn off the angiogenesis process. But cancer cells use this normal process for a nefarious purpose — creating an imbalance of angiogenesis activators that overrides the inhibitors and gives the nearby tumor ready access to a blood supply. This creates a vicious cycle of growth that allows tumors to grow faster than the body can respond.

In recent years, researchers have found that copper is a common denominator to several of the key factors that activate the angiogenesis process. Specifically, it acts as a co-factor, or helper, to molecules known as basic fibroblast growth factor (bFGF), vascular endothelial growth factor (VEGF), and angiogenin. Without copper, the molecules can't function and construction of blood vessels stops.

That's why TM makes such a good choice, Brewer explains. It binds with copper and protein, making a stable compound that can't be used by tumor cells or any other part of the body. Taken at mealtime, TM prevents the body from processing and absorbing the copper in food as well as the copper normally found in saliva and gastric secretions. Taken between meals, TM is absorbed into the blood and binds copper to blood protein. In either case, the TM-protein-copper complex does not interact with other biological molecules and is excreted.

The discovery of TM's potential effect on cancer grew directly out of Brewer's decades-long research on trace metals' importance to the body. He began by examining the role of zinc in sickle-cell anemia, a disorder of the red blood cells, and unexpectedly found that zinc acetate reduced the level of copper in the blood of some patients. This gave him the idea to test the compound's effect on the dangerously high copper levels in the systems of patients with Wilson's disease, a potentially fatal recessive genetic condition that strikes 5,000 teen-agers and young adults each year. Finding that zinc acetate brought the patients' dementia, drooling, slurred speech, temper outbursts and tremors under control if taken regularly, without side effects, he sought and received FDA approval for the compound.

But he needed a faster-acting compound to bring copper levels under control quickly. That compound turned out to be TM, now in clinical trials at the U-M General Clinical Research Center. To date, 63 Wilson's disease patients have come to the U-M for eight weeks of treatment with TM to lower their copper levels, then returned home to take zinc acetate and follow a copper-restricted diet to maintain their copper levels.

Merajver can be reached at smerajve@umich.edu; Brewer at brewergj@umich.edu.