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Drug Developed For Rare Disease May Help Millions More As Treatment

For Cancer, Autoimmune Diseases


Source: University of Michigan Health System

An anti-angiogenesis drug developed at the University of Michigan is

showing promise in studies of 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 began 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. Currently,

TM is involved in nine phase II clinical studies related to cancer,

with more planned.

But it doesn't end there. Brewer and colleagues are also looking into

the effect of TM on inflammatory fibrosis diseases such as pulmonary

fibrosis, cirrhosis, cystic fibrosis and psoriasis.

"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


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


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


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 adjusting

the dose of the TM.

Some of the TM trials that are currently in place or being planned at

UMHS and collaborating institutions include breast cancer, kidney

cancer, liver cancer, esophageal cancer, mesothelioma, idiopathic

pulmonary fibrosis, scleroderma, primary biliary cirrhosis and


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Hi Cary,

We went to to Uof M for my dad. WE seen a pulmonologist and I asked him about Dr. Brewer and how do we get an appointment with him, he didnt seem to interested in him because I dont think he knew too much about his theory. He said "oh yeah the copper man" you really cant get an appointment with him like you do with a doctor. I wish now that I had followed through with my instincts. I wasnt aware of his developments with fibrosis, had I known I definately would have tried to get dad into a trial, because it was the fibrosis that took my dad from us. Bottom line is go with your instincts, dont let anyone talk you out of something that you think may help you. Praying for you all.

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Hi Cathy,

The only thing your Onc was correct about is the fact that you can't see Dr. Brewer the same way as an ordinary doctor, but the Onc should have known TM can be obtained by any physician willing to prescribe it(which there are). Since my father started this treatment our doctor has talked to Dr. Brewer a few times on behalf of my father. I have known for quite some time that TM helps to prevent lung fibrosis(my father has not had chest radiation yet and hopefully will not have to). When my father had his Whole Brain Radiation I found out that TM can help prevent long term side effects(inflammation causing necrosis of the brain) that are commonly associated with radiation. TM can actually make the radiation treatment more effective. You can't feel guilty about not getting TM your Onc should have been more supportive and knowledgeable especially since he works right at UofM.


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