Failed Cancer Therapy Is Reborn

It is hard to read about new “cures” for cancer. Time and again our hopes are dashed by a dramatic announcement of a therapy that works in laboratory mice, only to fail miserably in human trials. Sometimes, however, the story turns around, and the failed approach turns up a winner after all. This week we were treated to such a happy ending.

The story begins in 1998, when Dr. Judah Folkman of Harvard University announced that he had succeeded in eradicating tumors in mice with a dramatic new approach to cancer therapy. Dr. Folkman’s approach follows up on a familiar observation made by many oncologists (cancer specialists), that removal of a primary tumor often leads to more rapid growth of secondary tumors. “Perhaps,” Folkman reasoned, “the primary tumor is producing some substance that inhibits the growth of the other tumors.”

Folkman succeeded in isolating a series of tumor-inhibiting substances, all of which proved to work by shutting off the tumor’s blood supply. To grow, a tumor must obtain from the body’s blood supply all the food and nutrients it need to make more cancer cells. To facilitate this necessary grocery shopping, tumors leak out substances into the surrounding tissues that encourage angiogenesis, the formation of small blood vessels. This call for more blood vessels insures an ever-greater flow of blood to the tumor as it grows larger.

Folkman’s tumor-inhibiting substances were “angiogenesis inhibitors,” chemicals that prevent expansion of a growing tumor’s blood supply. Cut off a plentiful supply of food and nutrients to fuel the production of new cancer cells and the tumor cells die, literally starving to death.

Folkman’s antitumor factors caused tumors in mice to regress to microscopic size, a result that electrified researchers all over the world. Unfortunately, getting Folkman’s angiogenesis inhibiting factors to work proved to be very touchy. Experiments would work well in some laboratories, in others not as well. Phase 3 clinical trials of seven such angiogenesis drugs all failed.

So what has happened to change this discouraging story? Researchers at Genentech, a drug development company, announced this week that a new approach to starving tumors had prolonged the lives of patients with colon cancer in a phase 3 clinical trail (that is, a trial with blind control groups designed to test the effectiveness of a drug administered to human patients).

Instead of attempting to isolate difficult-to-manipulate angiogenesis factors from cell cultures, the Genentech scientists created their own. Using genetic engineering, they produced a so-called “monoclonal antibody” they dubbed avastin. Avastin is an antibody protein designed to stick specifically to a protein in the blood called vascular endothelial growth factor (VEGF). VEGF is the protein which the body uses to trigger new blood vessel formation. Like coating a bicycle with cement, coating VEGF with avastin destroys its ability to carry out its blood-vessel-forming job.

Genentech set out to test their new drug avastin against colon cancer, the second-leading cause of cancer deaths in the United States. An estimated 147,500 new cases will be diagnosed in 2003.

In the avastintrial, some 400 colon cancer patients were given avastin in addition to standard chemotherapy, 400 others a placebo instead of avastin. All 800 patients had colon cancer that had already spread elsewhere in the body, an incurable condition. Detailed results of the phase 3 clinical trials of Avastin were announced with considerable enthusiasm by Genentech June 1 at a meeting of the American Society of Clinical Oncology in Chicago: Avastin improved colon cancer patients’ chance of survival by 50% over chemotherapy.

This result was suprising to many researchers, as the same drug, avastin, had failed in phase 3 trials treating breast cancer. It seems reasonable that the added life expectancy in these phase 3 trails comes not from any effect of avastin on the primary colon tumor, but rather by avasin’s inhibiting the establishment of secondary tumors elsewhere in the body. Why didn’t it work this magic against breast cancer? No one has any idea.

All cancers are not the same, as this result clearly demonstrates. That is why we need to remember not to get overly discouraged when a reasonable approach fails in clinical trial against a particular cancer. There is so much we don’t know, that a little tweaking, a slight change in target, can have dramatic results.

Genentech was rewarded by a 45% jump in its stock price after this week’s announcement. We were rewarded with another incremental improvement in cancer therapy. In the real world, stripped of hopeful enthusiasms, progress is made by such small steps.

©2003 Txtwriter Inc.

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