ANN ARBOR, MI - An anti-angiogenesis drug developed at the University of Michigan is being studied in three different disease families, including multiple forms of cancer. The drug, tetrathiomolybdate or TM, essentially wages war against copper, which serves to choke off tumor growth, fibrosis and inflammation.

U-M researcher George Brewer, M.D., who developed the drug, will present his findings to date and report on ongoing basic and clinical TM research at the 226th American Chemical Society national meeting Sept. 10 in New York. Brewer's presentation will be part of a one-day symposium on medicinal inorganic chemistry.

TM is being studied as a treatment for Wilson's disease, a rare genetic disease that causes toxic build-ups of copper. Recent phase III clinical data show TM is more effective than other treatments at reducing the disease's effects. Realizing the key role of copper in angiogenesis, Brewer and colleagues then began exploring treatments for cancer, including breast cancer, kidney cancer and liver cancer.

But it doesn't end there. Brewer and colleagues are also looking into the effect of TM on inflammatory fibrosis diseases such as cirrhosis and cystic fibrosis.

"TM has the potential to be a powerful tool in fighting a wide range of diseases. While it has literally saved the lives of young people with Wilson's disease, Wilson's is a rare disease. If early results in cancer and inflammatory diseases hold their promise through the next phase of trials, there's potential for this to impact a lot of people," says Brewer, Morton S. and Henrietta K. Sellner Emeritus Professor of Human Genetics at the University of Michigan Medical School.

Wilson's disease typically strikes young adults in their teens or early 20s. The condition causes copper to accumulate in the body at dangerous levels, and if left untreated can cause severe liver damage and neurological effects and eventually death.

Positive results of phase III clinical studies on TM in Wilson's disease were published last winter. Brewer is currently looking for a drug company to submit it for approval by the U.S. Food and Drug Administration as an orphan drug for treating Wilson's disease. Meanwhile, patients have come to UMHS from all over the world to receive treatment through the clinical trials protocol.

While the Wilson's treatment began to achieve success in the early 1990s, research at U-M and elsewhere started to uncover the role of copper in angiogenesis, or the formation of new blood vessels. This is a process that occurs normally in the body but becomes uncontrolled in cancerous cells. Researchers found copper was important to various molecules called growth factors that are necessary to the organizing process by which cells become part of new blood vessels.

That launched Brewer into a new direction with TM as an anti-angiogenesis drug. He began working with breast cancer researchers, particularly Sofia Merajver, M.D., at the U-M Comprehensive Cancer Center. In 2000, they published promising results of a pilot clinical trial. From there, many more trials have begun, some of which are now reporting positive early results.

"TM inhibits angiogenesis and growth factor by reducing the copper," Brewer says. "Essentially, the drug blocks the key signaling pathway, preventing tumor cells from sending signals to form new blood vessels, which thereby prevents or slows the cancer from growing or spreading."

TM is made up of the elements sulfur and molybdenum. These combined elements latch on to copper in the blood and to a protein called albumin. The three-part complex formed by this bonding is then eliminated by the body. For Wilson's patients, this brings high copper levels down to normal ranges. In cancer, it creates a mild copper deficiency, which is what inhibits the tumor growth.

And that led Brewer to consider whether TM would affect fibrotic diseases. In much the same way that copper deficiency inhibits the angiogenic effect in tumor cells, Brewer found it also inhibits transforming growth factor beta, or TGF-beta, the response that triggers the connective tissue growth. Additionally, studies suggest TM inhibits TNF-alpha, or tumor necrosis factor alpha, the response that triggers inflammation.

"When an organ is injured, the body overreacts, and doesn't properly regulate. This causes inflammation and fibrosis to over-respond, producing diseases. With TM, we're able to shut down the excessive inflammation and excessive fibrosis that causes much of the disease after an organ is injured," Brewer says.

TNF-alpha antibodies, sold as the commercial drugs Enbrel and Remicade, have been used in new treatments for autoimmune diseases such as rheumatoid arthritis and Crohn's disease. But this therapy requires regular injections of the antibodies. The next question on Brewer's plate is whether TM can do the job even easier.

"We have an oral pill that's shown to inhibit TNF-alpha in mice. The concept is that for whatever diseases these antibodies therapeutically benefit, TM should be tried," Brewer says. Studies are either beginning or in the planning stages for several autoimmune diseases.

One of the advantages to TM is that it carries few side effects. Studies to date show the primary side effect is copper deficiency from overtreating. This causes anemia, but is corrected by lowering the dose or stopping the TM treatment. In Wilson's patients, there is also a risk of liver damage. That also is alleviated by a drug holiday.

The University of Michigan has licensed the anticancer uses of tetrathiomolybdate to Attenuon LLC and the university has an equity interest in Attenuon. Brewer and Merajver have equity interests in Attenuon and are paid consultants to the company.

For more information on TM research at the University of Michigan Health System, call the Cancer AnswerLine at 800-865-1125 or visit www.cancer.med.umich.edu/contact.htm.

Written by: Nicole Fawcett

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