Growth Factor Lets Breast Cancer Evade New Drug

Insulin-like protein gives tumor cells a new lease on death

WEDNESDAY, Dec. 19, 2001 (HealthDayNews) -- Growth-promoting proteins that resemble insulin may determine whether some patients fail to respond to a new, potent breast cancer drug, Canadian researchers say.

The drug, called Herceptin, should in theory quash a select strain of breast cancer cells in all women who take it. But its actual performance is markedly worse, with about 70 percent of patients resisting the medication from the start or failing to respond to it over time, experts say.

Now, Canadian scientists say tumor tissue that should shrink in the presence of Herceptin can shrug off the drug by churning out insulin-like growth factor. Out-foxing this response could reduce resistance, they say. A report on the findings appears in the current issue of the Journal of the National Cancer Institute.

Herceptin, which is used alone or with other breast cancer drugs, won regulatory approval in September 1998 after studies showed that it could shrink tumors and prolong survival in patients whose tumors were rich in a gene called HER2. About 20 percent to 30 percent of the 193,000 women diagnosed each year with breast cancer over-express this gene, which regulates the growth of cells.

The drug, sold by Genentech, is the first compound for breast tumors derived from monoclonal antibodies, which are mouse proteins engineered to mimic their human counterparts. Because it is so specific, it has far fewer side effects than does conventional chemotherapy, experts say.

Even so, "the major issue with a lot of these new therapies is why they don't work sometimes," says Dr. Douglas Yee, a cancer specialist at the University of Minnesota in Minneapolis who is familiar with the latest findings. "Because [Herceptin is] directed against a specific target, it's a little curious why more patients don't respond."

In the latest study, Dr. Michael Pollak of McGill University in Montreal wondered whether insulin-like growth factor-1 (IGF-1) might have something to do with this failure to respond.

Earlier work, including his own, suggested that too much IGF-1 in the blood increases the risk of some cancers. "It was a bit of a speculative hypothesis, but if [cancer cells] want to escape from growth restrictions, they can do it by activating their IGF" signaling mechanisms, Pollak says.

The researchers analyzed cell colonies of two forms of human breast cancer.

One cell line, MCF-7/HER2-18, over-expresses receptor molecules that recognize HER2 and also has ones that respond to IGF-1. When receptors are at full strength, Herceptin can't keep the cells from dividing. But when the growth factor receptors were muzzled, Herceptin cut cell proliferation by 42 percent, the researchers found.

"If we just deprived the cells of IGF-1, all of a sudden the Herceptin became effective," Pollak says.

The other cell group, SKBR3, is rich in HER2 receptors but has very little IGF-1 activity. When exposed to Herceptin, cell growth fell, again by 42 percent. However, when the cells were tweaked to have more IGF-1 receptors and dosed with the protein, the cancer drug stopped working. Pollak's group was able to reverse that effect by adding a compound that mutes IGF signaling.

Pollak calls the results "pretty convincing lab evidence that IGF signaling is one way for a cancer cell to get around Herceptin." And, he says, it points to the possibility of reducing tumor resistance to the drug by blocking IGF-1 receptors. "Targeting more than one receptor at once may get us more clinical benefit," he says.

Yee, who has studied the role of IGF-1 in tumors, agrees that adding an anti-IGF compound to Herceptin might boost the cancer drug's effectiveness for some women. On the other hand, he says, it's likely that some patients resist the medication for other reasons, and there may be many more growth factors involved than IGF.

What to Do: To learn more about Herceptin, visit Genentech. For more on breast cancer treatment, try the American Cancer Society or the California Breast Cancer Research Program.

SOURCES: Interviews with Michael Pollak, M.D., professor of oncology, McGill University, Jewish General Hospital, Montreal; Douglas Yee, M.D., professor of medicine, University of Minnesota Cancer Center, Minneapolis; Dec. 19, 2001, Journal of the National Cancer Institute
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