Copper-Lowering Drug Stabilizes Advanced Cancer In Anti-angiogenesis Trial

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 issue of Clinical Cancer Research. The sixth 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 surprising 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 around the world. 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 the patients' copper levels. TM was originally developed for clinical use by George J. Brewer, M.D., a U-M human genetics professor, to treat people with Wilson's disease, a rare genetic disorder caused by excess copper. His work has shown TM to be the world's most potent anti-copper agent, and has also demonstrated that it is safe to use.

Aware of earlier research indicating that copper is important for angiogenesis, Brewer did work in the early 90's on animal cancer models treated with TM, with encouraging results. Then, he teamed up with Sofia Merajver, Ph.D., M.D., a molecular genetics researcher and oncologist at the U-M 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 from humans actually come 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 assess 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. For more information, call 1-800-742-2300, category 7882.

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."

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 it, they 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 power of TM to stop angiogenesis in cancer cells was clearly shown in a trial conducted by Brewer and Merajver using mice specially bred to have a 100 percent risk of breast cancer. The compound prevented cancer tumors from growing in all the mice, a remarkable achievement that encouraged the researchers to pursue the human trial. Animal research elsewhere using another copper-reducing agent was not as successful.

As reported in Clinical Cancer Research, the trial found that 120 milligrams of TM per day was the most effective dose of the three doses tested, bringing copper levels to the target of 20 percent of baseline without side effects. Brewer and Merajver call this level a "window" that allows the body's other copper-based reactions, such as red blood cell function, to proceed but starves tumors of the copper needed for angiogenesis. Patients who stop taking TM have normal copper levels again within days.

Of the six patients who reached the target copper level and remained on TM for more than 90 days, four are still alive after treatment periods ranging from 11 months to 21 months. Two others have left the study but are still alive after 6 and 17 months, respectively.

While not all patients in the U-M trial reached the 20 percent target within the 90-day period specified, the researchers believe that increased doses of TM will achieve this goal in future patients. Already, the first two patients in the new phase I/II trial have seen their cancer remain stable after more than five months of treatment.

"We also believe that the earlier TM is given in the progression of a patient's cancer, the better it should work," says Merajver. A 100-patient phase II trial of TM in patients who have recently completed conventional therapy for breast, prostate and kidney cancer, sarcoma and multiple myeloma is being planned for this year.

A full-scale toxicity test of TM will also begin shortly, though the compound has shown no toxic effects in dozens of Wilson's disease patients who have taken it to remove copper from their bodies. Toxicity data are required before TM can enter phase III clinical trials.

The U-M has filed for a new-use patent for TM in the treatment of cancer and other diseases that rely on angiogenesis. The University is currently in negotiations with a pharmaceutical company to fund further research, part of which will be directed at testing the efficacy of new compounds with similar copper-lowering effects.

The research was funded by Food and Drug Administration grants, gifts for Brewer's work on TM, National Institutes of Health grants for Merajver's basic research on mechanisms of copper-related angiogenesis, and donations to the U-M Comprehensive Cancer Center.

The discovery of TM's potential effect on cancer grew directly out of Brewer's decades-long research effort 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.