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New AmmunitionIn Cancer WarWonder drugs disarm proteins,with minimal side effects

New York Daily News - Sunday, May 20, 2001

A new family of wonder drugs that fight cancer - but appear free of devastating side effects - is coming on line, giving unexpected hope to sick patients and revolutionizing cancer treatment.
Like sirens luring enemy troops away from battle, the new drugs of man-made molecules and proteins do not kill the messengers that trigger certain cancers but garble and waylay their deadly instructions.

Dr. Leonard Saltz discusses the drug C225 with patient Cathy Saladino at Memorial Sloan-Kettering Cancer Center. "This is what we have been looking for, instead of drugs that cause cancer regression at the cost of a lot of healthy tissue," Dr. Joseph Bertino said, referring to the slash, burn and poison tactics of conventional surgery, radiation and chemotherapy.
Called EGF blockers, the drugs have "the whole cancer community very excited," said Bertino, head of molecular pharmacology and therapeutics at Memorial Sloan-Kettering Cancer Center in Manhattan.

EGF blockers treat a form of leukemia and are being developed to combat solid-tumor lung and colon cancer. Such drugs may become powerful weapons against head and neck, breast, ovarian and prostate cancers.
The new drugs are infinitesimally tiny agents that target cells bristling with receptors for EGF, or epidermal growth factor. The receptors are vulnerable points occurring on the outside of many cancer cells.

Rogue proteins that pop up and circulate (for reasons that are not always clear) use the receptors as gateways to a cell's interior. Once inside, the proteins transmit lethal messages that direct the cells to multiply wildly.

The new drugs are not cures, but "a crack of light at the door, opening a new treatment avenue," said Dr. Leonard Saltz at Sloan-Kettering, who is testing an experimental EGF colon cancer drug called C225. "We have to go through that door and see how far it takes us."

The ultimate goal may be long-term disease management, said Dr. Vincent Miller, Sloan-Kettering's principal investigator of an EGF receptor drug called Iressa, which treats the most common lung cancer.

Other EGF drugs seem to work best in combination with standard drug treatments, apparently disarming the disease enough to let the medicine work. Used with other drugs, Iressa led to "nearly complete resolution" of advanced lung cancer in one of 30 patients at Sloan-Kettering, Miller reported.

In another case, a dying man who had exhausted chemotherapy options got nine months of "good quality time" with Iressa. "I carry his X-rays around with me for when times get tough. It reminds us of why we forge ahead," Miller said.
The new smart-bomb drugs come in two models: monoclonal antibodies, which are proteins, and small molecule.

C225 is a monoclonal antibody that blocks EGF receptors outside cells. Result: The rogue proteins that float by can't penetrate the cell's perimeter to deliver their deadly message.
Of 120 patients who received C225 in trials, 22.5% showed a positive response when Sloan-Kettering's Saltz added it to their standard chemotherapy regimen.

"These were patients where we would expect a response rate of almost zero," he said.
Small-molecule drugs like Gleevec, Iressa and Tarceva slip directly into cells, where the wily and mild-mannered counterintelligence agents disrupt the messages emitted by rogue proteins.

Because the new medications work within the body's system, not against it, side effects are minimal. The most common: an acnelike skin rash. That, said Mary Lynn Carver at AstraZeneca, which developed Iressa, "makes sense, because it is an epidermal, or skin, growth factor.

"Small molecules also provide an advantage if the monoclonal antibodies aren't enough to stop destructive messages that have already gotten inside cells, said Dr. Nick Bacopoulous, head of Union City, N.J.-based OSI Pharmaceuticals, which makes Tarceva. The new treatments have evolved after decades of basic research, much of it in New York, as scientists have explored the peculiar ways that good cells turn bad. A crucial step was finding that certain receptors multiplied with certain cancers and, as they did, provided access for the bad proteins.

The new approach is changing how scientists think of cancer therapy. Drugs that target other receptors are in the works. Atrasentan, a small molecule, for example, targets endothelin A receptors expressed by prostate cancer cells.

But each cancer is different, Bertino said. Chronic myeloid leukemia involves just one abnormal protein and receptor, which made Gleevec's target very focused. Other cancers are more complex and less predictable.

So far, the targeted, smart-bomb approach is "brilliant," Bertino said, adding: "Now we are looking for other switches in other cancers that we can attack."

One Patient's 'Extraordinary' Recovery

Some of the new drugs already have yielded stunning benefits.
Victoria Reiter, 63, calls the EGF receptor drug she takes "absolutely extraordinary." An 18-month battle against chronic myeloid leukemia with conventional drug therapy left the Manhattan writer and translator bedridden.

"It was horrible for me and didn't do a damn bit of good." Reiter said. Tests showed her cancer had only worsened.

Early last year, she stopped treatment.
"I felt I didn't have much time left," Reiter said. Then her physician, Dr. Richard Silver at Weill Corner Medical Center, asked her to try an experimental drug, STI-571, now commercially known as Gleevec.

She began the new drug in February 2000. By May, Reiter could feel her body healing. By August, her bone marrow test showed no sign of cancer.

"I am absolutely filled with gratitude," said Reiter, who continues her daily Gleevec dose.
"There is no guarantee. This is remission, not a cure. But at this point the life I have been given back is wonderful. I am full of energy. I am no longer putting off the things I want to do." She is taking dancing classes.

The Latest Arsenal1.

1. C-225, ImClone Systems, Manhattan.
• Treats - Colon cancer.
• Stage - FDA approval possible by mid-2001.
• Side Effects - For 2% to 3% of patients, serious allergic reaction; two of three patients develop a skin rash.

2. Gleevec, Novartis Pharmaceuticals, East Hanover, N.J.
• Treats - Chronic myelogenous leukemia and gastrointestinal stromal tumors.
• Stage - FDA approval May 10 for leukemia.
• Side Effects - Nausea and diarrhea, occasional swelling and lowered blood counts - but few patients are forced to stop treatment.

3. Tarceva, OSI Pharmaceuticals (with Genentech and Roche), Uniondale, L.I.
• Treats - Cancer of the head and neck, lung and ovary.
• Stage - Possible FDA approval by 2003 or 2004.
• Side Effects - Temporary skin rash.

4. Iressa, AstraZeneca, Wilmington, Del.
• Treats - Lung cancer.
• Stage - Possible FDA approval in a year to 18 months.
• Side Effects - Rash, diarrhea, acne, some mild fatigue. No nausea.

5. Atrasentan, Abbott Laboratories, Chicago.
• Treats - Prostate cancer.
• Stage - Fast-track FDA status, possible approval by 2003 or 2004.
• Side Effects - Headache and runny nose, some swelling of legs.

For additional information, please contact:
Cancer Research & Treatment Fund
Phone: 212-288-6604
Fax: 212-288-7704 or 212-746-8246
e-mail: director@crt.org