Targeted Attack

Scientists declare war on a protein implicated in some stubborn forms of cancer

A rose may be a rose, no matter what you call it, but cancer does not follow the same rules. Although every cancer arises from an uncontrolled reproduction of cells, tumors can appear in nearly any body part. In different people, tumors in the same organ can arise from different cellular abnormalities. However, as scientists zero in on the molecular details of each type of cancer in an attempt to tailor treatments to its peculiar biology, they’re also looking for biochemical traits that groups of cancer cells share. They’re searching for a single treatment strategy applicable to many patients.

A promising new target of this sort is a receptor protein called EGFR, which has long been known to be overactive in a variety of tumors. The complicated story of how EGFR can cause normal cell division to go haywire is now beginning to come together. As scientists tease out the details, they are developing drugs that block EGFR, thereby reducing tumor size and lengthening people’s lives—if only for a brief time in a select group of patients.

A lot of hope is riding on the research, especially for treating lung cancer. That illness, notoriously difficult to treat, is responsible for more fatalities than any other cancer. About 60 percent of people diagnosed with lung cancer die within a year, and nearly 75 percent die within 2 years.

The quest to find EGFR inhibitors—drugs that block EGFR—hasn’t been smooth. One of the most promising drugs is made by AstraZeneca. In its fast-track process, the Food and Drug Administration in May 2003 approved that drug, called gefitinib (Iressa), for treating advanced non-small-cell lung cancer. This form of lung cancer is by far the most common one. But this past June, the drug didn’t prove effective in trials of patients with late-stage disease, and so it was taken off the market for new patients.

Now, researchers are conducting dozens of additional clinical trials to see whether gefitinib and related pharmaceuticals can be effective in people whose disease fits a certain biological profile.

Even though research into EGFR is in its early stages, insights about the receptor represent a major step forward for cancer treatment, says Jeffrey Settleman of Harvard Medical School in Boston. Fighting cancer, he says, has traditionally required chemotherapy and heavy doses of radiation, which kill cells indiscriminately rather than limiting their destruction to tumor cells. “It’s now possible to think about targeting all kinds of cancers with single-agent therapies that target specific proteins,” Settleman says.

Good gene gone bad

EGFR, also known as epidermal growth factor receptor, plays a critical role in cell division, survival, and migration. Regulation of these processes is important both during development and—in skin, intestinal-lining, and other cells that constantly renew themselves—throughout life, explains I. Bernard Weinstein, an oncologist at Columbia University.

EGFR is one of a broad class of receptors that straddle cell membranes. One end of EGFR sticks out of the cell. The other end pokes into the cell’s interior.

When one of several specific proteins, most commonly EGF (epidermal growth factor) or TGF-alpha (one of the so-called transforming growth factors), binds to the external portion of the receptor, it pairs with an identical or a similar receptor nearby in the cell’s membrane. This coupling causes the internal portion of the receptor to bind to a series of proteins within the cell. That biomolecular sequence signals the cell to survive, divide, or migrate.

Since 1984, researchers have noted that EGFR is overactive in many tumors in the lungs, prostate, colon, and other tissues. At first, it was unclear whether the increased activity was causing the cancers or whether that activity was simply a consequence of a more fundamental tumor-generating process.

In the past year or two, researchers have begun to investigate that question. In some tumors, they have found, there is an abundance of EGFR protein, indicating that the EGFR gene that codes for it is pumped up beyond its normal activity within the tumor cells. Experiments have revealed extra EGFR activity in 20 to 80 percent of all solid tumors, Settleman says.

In other tumors, it’s the proteins that bind to the outside of the receptor that appear to be overabundant.

Mutations in the EGFR gene have moved to center stage. In two separate but almost simultaneous reports, one in the May 20, 2004 New England Journal of Medicine (NEJM), and the other in the June 4, 2004 Science, researchers described EGFR mutations that make cells replicate uncontrollably.

Settleman, who was part of the team that published the NEJM study, followed those reports with a paper in the Aug. 20, 2004 Science, in which he and his colleagues chronicled the molecular details of EGFR mutations.

Overall, he says, scientists have identified some 35 mutations that can cause EGFR protein activity to spin off track, and three or four mutations are especially common. Settleman estimates that 10 percent of U.S. lung cancer patients have at least one EGFR mutation.

So far, most of the research on EGFR mutations has focused on people with non-small-cell lung cancer. In the Sept. 7, 2004 Proceedings of the National Academy of Sciences, scientists reported that nonsmokers who develop lung cancer are far more likely to have EGFR mutations than are smokers who develop the disease (SN: 5/7/05, p. 302: Available to subscribers at Novel drug may take on lung cancer; 9/11/04, p. 164: Available to subscribers at An Exploitable Mutation: Defect might make some lung cancers treatable).

Among people with lung cancer, women have higher rates of EGFR mutations than men do, and Asians have higher rates than other geographic groups. These genetic anomalies don’t appear to be hereditary. Instead, they seem to be spontaneous mutations that occur more frequently among certain people.

Those patterns may explain why gefitinib and similar drugs counter cancers in some patients but not in others. In 2003, before the mutations were discovered, pharmaceutical companies began producing drugs that block the internal portion of the receptor and prevent it from sending growth signals.

Gefitinib, the first such drug, reduced tumor size in lung cancer patients and boosted their survival in some trials. The drug seemed so effective that the FDA accelerated its approval while the drug was still in phase II trials, normally a midpoint in the approval process. Approval of Genentech’s erlotinib (Tarceva), which works in the same way as gefitinib does, followed in November 2004.

Later, larger trials of gefitinib weren’t as impressive, and gefitinib was taken off the market for new patients. Erlotinib proved just effective enough to remain on the market.

Surprisingly, the drugs seemed successful in twice the proportion of people in Japan and other Asian countries as they did in the United States. The explanation, it now seems, is that people with EGFR mutations respond best to these drugs, and a higher proportion of people have the mutations in Asia than in the United States.

Reanalyses of the results of clinical trials have shown that EGFR mutations occur in 80 percent of people who improve with the drugs but in only 6 percent of people who don’t benefit, Settleman says. The improvements include tumor shrinkage and longer survival.

Settleman and other researchers suspect that if the trials had included only patients with EGFR mutations, the drugs would have shown a clear benefit, and the FDA wouldn’t have opted to yank gefitinib from the market.

“To be honest, we’re disappointed,” says thoracic oncologist William Pao of the Memorial Sloan-Kettering Cancer Center in New York. “We think Iressa does benefit some patients.” The apparent difference in effectiveness between gefitinib and erlotinib may simply indicate that the erlotinib trials happened to include more people with the mutation.

Studies are under way to parse the differences in past trials and to collect new data from people known to have or not to have EGFR mutations.

Cancer’s own addictions

Scientists are beginning to think that gefitinib and related drugs work best in people with mutated EGFR because their cancer cells require altered receptors for their survival. “In that sense, they’re addicted to them,” says Weinstein. He points out that normal cells don’t rely on EGFR as much.

Even among lung cancer patients whose cell membranes are studded with mutant EGFR, however, the new drugs aren’t a panacea. Although some patients go into remission for years, tumors reappear after an average of 5 months, Settleman says. After that, gefitinib and erlotinib have no power to control the cancer.

In one case, a patient’s lung cancer disappeared for 2 years after he started taking gefitinib, only to return in a gefitinib-resistant form. Researchers at Harvard and other institutions described this patient in the Feb. 24 NEJM.

“Understanding why cancer patients are developing drug resistance is important because then we can figure out how to overcome it,” Pao says. Two groups of researchers, including Pao’s group, recently looked at a total of seven lung cancer patients who had received gefitinib or erlotinib and had suffered relapses. In four of these patients, the researchers identified a single-nucleotide change in the EGFR gene in the neighborhood of the mutations that make a cancer susceptible to the drugs. No mutation turned up there in the three other patients.

Weinstein describes the drug-resistance mechanism in terms of addiction. “The tumor was so dependent on the [EGFR] gene that the only way to escape and grow again was to mutate the very same gene to resist the drug,” he says.

Several groups of researchers are now working to prevent this escape by developing a new class of drugs, known as irreversible EGFR inhibitors, that latch on to EGFR with stronger, longer-lasting chemical bonds than those by which gefitinib and erlotinib attach.

“We suspect that a mutation that prevents binding of a reversible drug, such as Iressa [gefitinib], may not be sufficient to overcome the higher-affinity interaction of an irreversible inhibitor with EGFR,” Settleman says.

Daniel Haber and his colleagues at the Massachusetts General Hospital Cancer Center in Boston are getting encouraging results with an irreversible inhibitor called Hki-272. Made by Wyeth, the drug is undergoing phase I trials at multiple sites. Several other irreversible EGFR inhibitors are in similar stages of development for treating lung cancer.

In tumor cells that have no mutations in the EGFR gene, different types of drugs are proving to be more useful than gefitinib and erlotinib. For example, cituximab (Erbitux) was approved in February 2004 for treating colon cancer. Cituximab is an antibody that binds to the external portion of EGFR instead of to the internal part, as gefitinib and erlotinib do. This bottles up the receptor so that the proteins that normally would activate it can’t latch on.

Cituximab is also showing promise in trials for head-and-neck cancers, says Janet Dancey of the Cancer Therapy Evaluation Program at the National Cancer Institute in Rockville, Md.

Choose your organ

The National Cancer Institute is sponsoring more than 80 clinical trials around the world on drugs that affect the EGFR protein, Dancey says. Among these are trials that are testing whether gefitinib, erlotinib, and cituximab work best on their own or in combination with chemotherapy or other drugs.

Some trials are exploring which tumors respond to EGFR-focused drugs. “It may be that for any classically defined breast, colon, or lung cancer, there is a group of patients with tumors that rely on EGFR signaling for cancer growth,” Dancey says. EGFR mutations have been detected in cancers of the breast, colon, lung, and brain, but not in other forms of the disease.

There are also data that indicate why some groups of patients with EGFR-gene mutations may never benefit from gefitinib-style drugs. For example, Pao notes, one study has shown that mutations in a gene called K-RAS makes tumors immune to all the drugs that act on EGFR.

Most experts say that the future of cancer treatment will be based on individual genetic testing and a multipronged attack. In the battle against a cancer, physicians might slam EGFR and all proteins that interact with it, while simultaneously hitting other cancer-related genes and proteins.

Weinstein says that as details about the EGFR protein’s role in cancer coalesce into a bigger story, he hopes that treating the many forms of cancer will become as routine as fixing a broken television set. Just as with any new technology, it may be only a matter of time before the experts—in this case, oncologists—fine-tune their skills.

“If the TV set was broken, you could kick it,” Weinstein says, “but you’d be much more effective if you understood how the machine works and then fixed the parts that are malfunctioning.”

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