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Some Aim to Fix the Genes Themselves

Staff Reporter of THE WALL STREET JOURNAL

	Footnotes

 
[The following article appeared in THE WALL STREET JOURNAL, issue of May 6, 1998.]

Reprinted by permission of THE WALL STREET JOURNAL

Ever since scientists learned over a decade ago that cancer is the result of defective genes, they have dreamed of shutting down tumor growth simply by replacing the bad genes with good ones.

Researchers at two biotech companies and a pharmaceutical giant believe they are close to making that dream come true, at least for some patients.

In two weeks, scientists will present results of several studies showing, for the first time, that cancer growth in severely sick patients can be stalled through an innovative method of repairing damaged genes. If the initial studies of this "cancer gene therapy" in about a hundred patients hold up, one of the companies, closely held Introgen Therapeutics Inc. of Austin, Texas, believes its technique may be available to doctors in two years.

"We’re racing as fast as we can to prove our method works," says David Nance, chief executive of Introgen, which is working with M.D. Anderson Cancer Center in Houston. "If all continues to go well, we think we will be the first on the market with a cancer gene-therapy product. We’re aiming for the year 2000."

The technique is based on the knowledge that altered genes play a pivotal role in the underlying mechanism of much disease. But gene therapy is a highly controversial and much-criticized idea. Many drug makers believe it can’t be done in large enough doses to work or that it can’t work without causing toxic side effects. Hence, the very first human tests to, quite literally, repair the broken genes that drive cancer growth are being watched closely.

"Until recently, I thought gene therapy was science fiction, something to fantasize about. Maybe it isn’t," says Bert Vogelstein, a top cancer-gene scientist at Johns Hopkins Oncology Center in Baltimore, who isn’t involved in the gene-therapy studies. The three separate trials are being conducted by Introgen, Schering-Plough Corp. and Onyx Pharmaceuticals, a California biotech company.

Jack Roth, an M.D. Anderson doctor who is spearheading Introgen's trials and helped found the company, says initial human tests are aimed at trying to "prove the principle—that it's possible to stop tumor growth cold, perhaps even destroy the tumors totally, by injecting them with a tumor-suppressing gene." Combined, the trials have involved only a few hundred patients, and gene therapy countered cancer in only a small portion. Still, Dr. Roth is "encouraged by our very first efforts."

Introgen and the others are exploiting a discovery made in the late 1980s about a "suicide gene" called p53. It plays a critical role in controlling normal cell growth. When cells divide, p53 makes certain that all the genes are reproduced accurately. If there are errors in the genes' structure, p53 literally halts the cell-dividing process until the mistakes can be fixed—or forces the flawed cell to kill itself off.

But if p53 itself is damaged—perhaps by smoking, excessive sunlight or toxic-chemical exposure—the errant cells divide furiously until they become a tumor.

In the early 1990s, Dr. Roth and others witnessed test-tube experiments showing that inserting p53 into cancer cells stopped the dangerous dividing process. Vowing to try this approach in people, Dr. Roth, whose specialty is treating cancers of the head and neck area, borrowed techniques from scientists who inserted genes into modified viruses to try to fix inherited diseases such as cystic fibrosis.

Animal tests completed in 1996 showed that a modified virus carrying the p53 gene could significantly halt tumor growth and sometimes eliminate the tumor. Last year, Introgen completed Phase I safety tests in 94 patients. The tests were also designed to test the principle of whether p53 could penetrate the tumor and begin restraining cell growth—and it did. Tumor growth was stalled outright or reversed in 10 patients who had failed to respond to any previous cancer treatments. And in two patients diagnosed as terminally ill, tumor growth halted and hasn’t resumed for more than a year.

Introgen, whose research is backed by France's Rhône-Poulenc SA, now is doing efficacy trials in about 100 patients with a variety of tumors. So is Schering-Plough, in separate tests. Researchers hope to expand those tests in the final Phase III trials next year, combining gene therapy with traditional chemotherapy.

View larger version (88K): [in this window] [in a new window]   Gene Therapy. Cancer doctors are attempting to replace defective versions of the p53 gene that cause tumor growth through an innovative technique called cancer gene therapy.

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