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Herceptin Fights Aggressive Breast Cancer on Several Fronts

Antibody blocks blood vessel growth to tumors on more than one level, study finds

THURSDAY, March 21, 2002 (HealthDayNews) -- A single antibody may be all that's needed to slow down a particularly aggressive kind of breast cancer.

A new study by researchers in Boston reports that Herceptin shrinks blood vessel systems that support tumors in mice. It does this by simultaneously dampening chemicals that boost blood vessel growth and increasing chemicals that interfere with vessel growth. The finding appears in today's issue of Nature.

Although the study is preliminary, the researchers say it could raise the potential for a single anti-cancer agent that acts on many fronts to fight blood vessel growth to tumors.

Current drugs target only one chemical at a time, and tumors become resistant, creating a need for drug "cocktails" to treat breast cancer.

Every year, more than 203,000 American women are diagnosed with breast cancer, and 40,000 die from the disease. It's the second-leading cause of cancer death in women, although rates have declined steadily because of earlier diagnosis and better treatment.

The U.S. Food and Drug Administration approved Herceptin in September 1998 for the treatment of metastatic breast cancer. A genetically engineered antibody, Herceptin binds to a protein called human epidermal growth factor receptor-2 (HER2), which is produced in excess amounts by roughly 30 percent of metastatic breast cancers. This group of tumors is typically aggressive, and resistant to other therapies.

Senior investigator Rakesh K. Jain, director of the Steele Laboratory for Tumor Biology at Harvard Medical School in Boston, studied genetically engineered mice with human breast cancer tumors.

He and his colleagues found Herceptin blocked the HER2 receptor, slowing angiogenesis -- or blood vessel growth -- to the tumor. It reduced production of chemicals that stimulate blood vessel growth to tumors and triggered the release of chemicals that interfere with this same blood vessel development.

In the study, tumor blood vessels in mice treated with Herceptin showed significant reductions in diameter and volume, but not in length, compared to mice treated with a placebo.

The growth rate of tumors in the mice treated with Herceptin was also slowed, and mice that received the treatment lived longer than animals that received a placebo.

To find out how Herceptin worked, the researchers measured the activity of 23 angiogenesis-related genes in the tumors. They found that production of four blood vessel growth-promoting chemicals was reduced at the same time as production of an anti-angiogenesis chemical was boosted.

Jain says the findings could have important implications for cancer treatment.

"In the future, we will create profiles of a [patient's] tumor, as to whether you need 10 angiogenic or 20 angiogenic inhibitors," Jain explains. "Once we know that profile … then we can combine those."

"You cannot just block one angiogenic molecule. That will eventually fail, because the tumor can switch from one molecule to the next," Jain says. "What we therefore need is a cocktail of antibodies or anti-angiogenic agents."

He says Herceptin acts as a cocktail by controlling several chemicals that influence blood vessel growth.

Mark X. Sliwkowski is a senior scientist in molecular oncology at Genentech Inc., which makes Herceptin in an intravenous form.

"It's striking that we're talking about targeting one particular type of receptor pathway, the HER2 pathway, and that it would have such a profound effect on this angiogenesis pathway," Sliwkowski says.

He cautions that the findings were preliminary and involved mice, but adds that the key clinical implication is the potential for customized cancer treatment.

"Based on these findings, it might be possible to actually get a lot more [potent] chemotherapy into tumors when patients are on Herceptin therapy," Sliwkowski says.

"With the development of these targeted therapies, these biological therapies may either extend the benefit we already see with chemotherapy, or they may even replace that kind of therapy," he says.

He stresses that while a cure is unlikely in people with advanced cancer, "the hope is that if we begin to apply these therapies earlier in the course of these various types of cancer, that the benefit will be far greater."

What To Do

You can check out more about Herceptin from the U.S. Food and Drug Administration or Genentech.

Find out about breast cancer from the American Cancer Society.

SOURCES: Rakesh K. Jain, Ph.D., professor, tumor biology, director, Steele Laboratory for Tumor Biology, Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston; Mark X. Slikowski, Ph.D., senior scientist, molecular oncology, Genentech Inc., South San Francisco; March 21, 2002, Nature
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