Targeted Therapies Begin to Make Dent in Cancer’s Armor
Published: June 18, 2005
The dream of targeted cancer therapy is irresistible:
Understand the machinery that drives tumors. Build a pharmaceutical smart bomb to destroy that machinery. Spare patients from the sometimes deadly ravages of chemotherapy, which indiscriminately attacks all of the body’s rapidly dividing cells and leaves patients bald, sick and weak.
In short, create the magic bullet that cures cancer.
But as scientists have chased targeted therapies for the past 20 years, cancer has refused to cooperate.
“Biology is much more complex than we envision, and although our models are straightforward, our patients and their diseases are not,” says Dr. Lee Ellis, a University of Texas researcher who has studied targeted therapy for more than a decade. “If the mechanisms were as straightforward as we originally thought, we’d be much further along.”
And yet, though they have not been the panacea scientists once hoped, targeted therapies are finally, imperfectly, emerging.
One targeted drug, Gleevec, drives a rare - and formerly deadly - strain of leukemia into remission.
Herceptin, a targeted breast cancer drug, cut the risk of relapse in half for patients who had early stage cancers surgically removed, scientists announced last month at a major cancer conference.
In other studies presented at the same conference, targeted drugs combined with chemotherapy extended the survival of patients with some of the deadliest forms of the disease, including lung, colon and pancreatic cancer.
“Right now we have a few targeted agents. In the next 10, 20, 50 years we’ll have hundreds more,” says Dr. Brian Druker, one of Gleevec’s developers. “It’s no longer a matter of ‘if’; it’s a matter of ‘when.’”
There will never be a single cure for cancer because cancer is not a single disease. Indeed, the more scientists learn about cancer, the more diseases it seems to become - first dozens, then scores, then hundreds.
The same treatment might knock out one patient’s cancer altogether and leave another seemingly identical cancer unscathed, says Dr. W. Jarrard Goodwin, director of the Sylvester Comprehensive Cancer Center at the University of Miami.
“When we treat 100 patients the same way, why are 60 of them cured and 40 are not?” he asks. “We’re beginning to divide those up and see that the 40 percent that recur are different cancers, genetically. They look the same under the microscope, but they’re different - they have different mutations within the cells.”
Insight into genetic differences in breast cancer led to the success of Herceptin, which in 1998 became the first of the new targeted therapies to win approval. The drug disables a protein called HER-2 that plays a key role in about 25 percent of all breast cancers. Doctors use a molecular test to determine whether a patient’s cancer falls into that 25 percent.
Like many new drugs, Herceptin was initially approved for only the sickest patients, who were unlikely to be saved by existing treatments.
The drug helped those patients live longer - 79 percent who had Herceptin and chemotherapy survived for at least one year, compared with 68 percent who had chemotherapy.
The results announced in May were far more dramatic.
In a study of more than 3,000 women whose early stage cancers were surgically removed, those treated with chemotherapy and Herceptin had a 15 percent chance of recurrence after four years. Those who had chemotherapy alone had a 33 percent risk of recurrence.
“This is the most important breast cancer discovery in the last 20 years,” said Dr. Sandra Franco, co-director of the Memorial Breast Cancer Center in Hollywood and one of the trial’s investigators.
Researchers are still evaluating what the data mean for survival rates for the 50,000 women diagnosed each year with the form of breast cancer sensitive to Herceptin. Dr. Stefan Gluck, a breast cancer specialist at the University of Miami, said the drug will save thousands of lives each year.
Other targeted therapies have also showed promising, though less dramatic, results. Drugs that prevent the creation of new blood vessels essential for tumor growth extended by a few months the lives of patients with late-stage breast, colon and kidney cancer.
Studies are now underway to examine whether those drugs will, like Herceptin, help save patients with earlier-stage cancers. Researchers are also working to figure out which genetic traits make tumors more likely to respond to particular drugs.
Many cancers are driven by more than one genetic defect; doctors are trying to determine whether combinations of targeted therapies in some cases work better than any one drug.
In most studies, targeted therapies have been used with conventional chemotherapy - a disappointing result given the original hope of eliminating cancer without chemo, says Dr. Leonard Saltz, a researcher at Memorial Sloan-Kettering Cancer Center in New York.
“We were going to get rid of these drugs that make people nauseous and make their hair fall out. That has not happened,” he says. “So Plan B has been if you can’t beat ‘em, join ‘em - marry targeted therapies to standard chemotherapy. The good news is the targeted therapy plus the chemotherapy works better than chemotherapy. The bad news is you still have to give chemotherapy.”
Many targeted therapies also have serious side effects of their own. Herceptin can cause heart problems; Avastin, which prevents the formation of new blood vessels, causes fatal internal bleeding in rare cases.
Yet for most cancer patients, the potential benefits outweigh these risks. And as doctors better understand the genetics of cancer, they will get better at developing and prescribing drugs that are both safer and more powerful, Druker says.
“If you take your car to a mechanic and they don’t know what’s broken, they can look inside and see all sorts of parts and replace any number of parts. Any one of the parts is a targeted therapy,” he says. “We’re in an era where we’ve just lifted up the hood and were looking at all these parts. We’ve got to get to the era where we know what’s broken.”
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