NEWS

Cutting Copper Curbs Angiogenesis, Studies Show

Cori Vanchieri

With the spotlight focused on angiostatin, endostatin, and a few other popular angiogenesis inhibitors, a handful of researchers are quietly targeting a trace element that appears to be crucial to tumor blood vessel growth—copper. Early patient studies are showing tumor response and low toxicity.

"We are learning that copper status is critical to the function of the angiogenic growth factors," wrote Steven Brem, M.D., in a 1999 article in Cancer Control. Vascular endothelial growth factor, basic fibroblast growth factor, tumor necrosis factor-{alpha}, and interleukin 1 are all copper dependent, said Brem, program leader of neuro-oncology at the H. Lee Moffitt Cancer Center in Tampa, Fla.



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Dr. Steven Brem

 
The list grows longer with interleukin 8, SPARC (an extracellular matrix binding protein), and angiogenin, said Sofia D. Merajver, M.D., Ph.D., associate professor of internal medicine at the University of Michigan in Ann Arbor.



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Dr. Sofia D. Merajver

 
Brem points to studies in humans and animals that show serum copper levels are associated with tumor incidence, tumor burden, malignant progression, and recurrence in Hodgkin’s lymphoma, sarcoma, leukemia, and cancers of the cervix, brain, breast, liver, and lung. Copper metabolism is upregulated, and the extra copper is transported to tumor tissue.

When copper levels are reduced, the tumors stop building new blood vessels to bring in nutrients and oxygen. Without copper, the tumors eventually stop growing, and in some cases, even shrink. And it can be done with few toxic effects. "There is a window at which copper levels are low enough to block angiogenesis but not so low that they harm more essential cellular processes," Merajver said.

Early Promise

Brem and Merajver are running early-phase clinical trials of different approaches to reducing copper levels.

Merajver’s group is testing tetrathiomolybdate (TM), a drug developed by George J. Brewer, M.D., professor of human genetics and professor of internal medicine at the University of Michigan. Brewer had been using TM for patients with Wilson’s disease, a genetic disorder that results in abnormal copper levels.

Brewer and Merajver found that TM was effective in impairing the growth of new mammary tumors in HER2/neu transgenic mice. In a phase I clinical trial in 30 patients with metastatic cancers, the therapy achieved stable disease in five of six patients who were copper deficient for at least 90 days. Some of the patients have been on the therapy for more than 2 years.

Unfortunately, the drug took about 8 to 10 weeks to substantially reduce copper levels, and some patients’ advanced disease progressed before copper levels dropped low enough. The University of Michigan researchers have since found that higher doses of TM can achieve copper deficiency sooner—within 3 to 4 weeks.

"I think this is going to be a good approach compared to others, because it has the potential of affecting a fairly large number of angiogenic promoters, while a lot of other [inhibitors] are hitting single molecules; you can give it orally, unlike some other angiogenic inhibitors; and it is very nontoxic," Brewer said. "It does look very good in a wide variety of tumors, but these are all preliminary results."

They will begin recruiting in August for phase I/II studies of TM in renal cell cancer, multiple myeloma, and hepatocellular carcinoma. A fourth trial in mesothelioma will be carried out with the Karmanos Cancer Institute in Detroit.

Drug Plus Diet

Penicillamine is the copper chelator of choice for Brem and colleagues at the NABTT Brain Tumor Consortium, headquartered at Johns Hopkins Hospital in Baltimore. They are testing the drug plus a low-copper diet in patients with newly diagnosed glioblastoma, a brain tumor that aggressively builds networks of new blood vessels to support its growth.

In the phase I/II study, after as much of the tumor as possible is surgically removed, the patients begin radiotherapy and daily doses of penicillamine. They also must steer clear of an eclectic list of foods, including shellfish, white and whole wheat breads, chocolate, organ meats, and bananas.

All 40 patients have been recruited. So far, the approach is effective in lowering serum copper, compliance with the diet and medication is good, and no severe toxicities have occurred, Brem said. A few patients have experienced disease stabilization and one has had a complete response, but the actual impact on recurrence and survival will not be known for a year. Brem speculates that one mechanism by which copper reduction could limit tumor growth is to make radiation more effective, as has been shown in experimental models combining antiangiogenesis and radiation therapy.

‘Difficult Tumors’

"These glioblastomas are difficult tumors. Current therapies are not effective," said Stuart Grossman, M.D., professor of oncology, medicine, and neurosurgery at Johns Hopkins Hospital and director of the NABTT Brain Tumor Consortium. "It would be foolhardy to say that if we just lower people’s copper, we could cure these tumors. But if we could show that lowering copper delays when the tumors recur and patients survive longer," perhaps other effective therapies could be added.

Richard S. Kaplan, M.D., program director for brain tumor research at the National Cancer Institute, is cautious about saying too much too soon. "I think it is too early to make anything out of what we know clinically at this point. It’s a theoretically promising approach."


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