NEWS

For EGFR Research, New Targeted Drugs Mean New Questions

Brian Vastag

In the early 1980s, a pair of researchers at the University of California at San Diego had an idea that was ahead of its time. John Mendelsohn, M.D., and Gordon Sato, M.D., had been studying a cell-surface molecule, the epidermal growth factor receptor (EGFR), that appeared to be a key element in oncogenesis. If they could shut down the receptor, they thought, maybe they could shut down cancer, too. So the team borrowed a motif from the body's immune system and built an antibody—a daunting task then—that clamps onto EGFR. Mouse experiments showed the soundness of their theory: Shutting down the receptor indeed halted the spread of cancer.

Twenty-five years later, the human version of that antibody is now an FDA-approved treatment for lung cancer, Erbitux (cetuximab). In the interim, scientists and grants flew toward EGFR as researchers struck on its role as all-around bad actor in out-of-control cell growth. EGFR became, in effect, the receptor that launched a thousand labs.

"A lot of people ask, ‘Why this system?’ " said H. Steven Wiley, Ph.D., from the Pacific Northwest National Laboratory. "It's the prototypical receptor system. We've been studying it for almost 50 years." As clinical trials of anti-EGFR therapy began in the 1990s, the concept generated huge excitement. However, the pivotal trials ultimately proved disappointing, with only a fraction of patients responding to therapy.

Illuminating Cancer

Nevertheless, researchers have repeatedly cited EGFR research as a key to illuminating the murky processes by which normal cells turn cancerous. At least five different growth factors dock with EGFR, and depending on the configuration and duration of binding, these proteins trigger several responses: cell proliferation, the formation of new blood vessels (angiogenesis), and inhibition of cell death.

In a normal cell, these processes play out on a tightly regulated schedule. But when a cell begins making too much EGFR, the growth signals get louder. Soon, they are nearly all the cell can hear. "Normal cells respond to a variety of partially overlapping signals," said Wiley. "But cancer cells rely on a few enhanced signals, such as those generated by EGFR." The result: haywire growth, cellular immortality, and quickened angiogenesis.

Researchers now know that EGFR-driven mutagenic forces affect many solid tumors. Head and neck cancer lead the way, with about 95% overexpressing EGFR. Depending on methodology, estimates for other types of tumors vary widely. Best estimates show EGFR overexpressed in at least half of colorectal, breast, prostate, ovarian, and lung cancers. "Every cell has EGFR, of course. Whether or not the cell becomes malignant is simply a question of how much EGFR," said Roy Herbst, M.D., Ph.D., chief of thoracic oncology at the University of Texas M. D. Anderson Cancer Center in Houston.



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Roy Herbst

 
Tumors with excess EGFR tend to be difficult to treat. "Overexpression [of EGFR] has been associated with poor prognosis and slow response to treatment again and again," said Carolyn Sartor, M.D., assistant professor of radiation oncology at the University of North Carolina School of Medicine.

As cancer researchers realized how frequently EGFR goes awry, they followed Mendelsohn and Sato's lead and began developing drugs to shut it down. First attempts to push the antibody into the clinic failed, but in the early 1990s, biotech startup ImClone acquired rights to the research. The company began clinical trials in 1995, and soon two other companies began their own trials of anti-EGFR antibodies. All three monoclonal antibodies work by clamping down on the "cup" of the receptor that sticks out of the cell, thereby blocking growth factors that normally trigger a cascade of signals that ultimately arrive at the cell nucleus.

In the 1990s, the field of anti-EGFR therapeutics expanded with a second approach. Whereas antibodies hit the receptor "high" (outside the cell), small molecules can hit it "low" (inside the cell). EGFR signals the nucleus through a series of proteins called tyrosine kinases. Researchers reasoned that blocking these signals—which grow in strength as a cancerous cell produces ever more EGFR—might also inhibit tumor growth. The first two EGFR tyrosine kinase inhibitors, Iressa (gefitinib) and Tarceva (erlotinib), received FDA approval last year. These two small-molecule drugs can be taken orally, whereas the bulkier monoclonal antibodies must be delivered intravenously.

But as in the phase III trials of cetuximab, only a fraction of patients—between 12% and 27%—responded to gefitinib and erlotinib in pivotal trials. Researchers responded by quickly identifying several mutations that appear to predict response to anti-EGFR drugs. In this issue of the Journal (see article, p. 643), Federico Cappuzzo, M.D., and colleagues at the University of Colorado Health Sciences Center add to the bounty. With the goal of developing a practical clinical test for patient selection, the team measured several EGFR-related factors in 102 patients with non–small-cell lung cancer. It turns out that patients with large amounts of the EGFR protein show better response rates to therapy—36% improved, whereas only 3% of patients with lower amounts of the protein got better.

Still, as the National Cancer Institute's Frederic Kaye, M.D., writes in an accompanying editorial (see editorial, p. 621), researchers are just beginning to untie complexities within the EGFR signaling system that affect drug response. "Unfortunately," he writes, summarizing several lines of research, "it appears that it may be easier to accurately predict drug resistance than drug efficacy."

As researchers improve patient selection with first-generation EGFR drugs, a second generation is already headed for the clinic. Last year, researchers at the Melbourne, Australia, branch of the Ludwig Institute for Cancer Research launched a phase I trial of an antibody that can distinguish between EGFR on normal cells and EGFR on cancerous cells. Initially intended as a treatment for glioblastomas, researchers only serendipitously discovered the discriminating abilities of 806, the code name for the antibody.

"Although the anti-EGFR antibodies on the market show antitumor activity, they are far from ideal," said Andrew Scott, M.D., head of clinical drug development at LICR-Melbourne. Scott envisions attaching a "lethal agent" to 806 to deliver it specifically to cancer cells. "We could avoid toxicities with 806 this way," said Scott.

Another group at the University of California at Los Angeles is also trying to target brain tumors, but with RNA. The blood–brain barrier shuts out large molecules such as antibodies, rendering cetuximab and its cousins useless against brain tumors. So William Pardridge, M.D., and colleagues struck on a novel approach—smuggling RNA across the barrier to interfere with EGFR production. Small globs of fat called liposomes ferry snippets of EGFR-specific RNA into the brain. The single-stranded RNAs then seek out, bind to, and silence messenger RNA as it streams out of the cell nucleus. The result: reduced production of EGFR. The work is still preclinical, but Pardridge said mice treated with the RNA survive twice as long as control subjects.

In the end, though, experts predict that anti-EGFR therapies will be most effective when combined with traditional chemotherapy, radiation, or with each other. Sartor said that there is compelling evidence that anti-EGFR drugs enhance tumor sensitivity to radiation and chemotherapy. And one team has found that combining an anti-EGFR antibody with a small-molecule tyrosine kinase inhibitor hits the receptor "high and low." Last fall, Paul Harari, M.D., associate professor of human oncology at the University of Wisconsin School of Medicine, and his team published a preclinical study that combined the antibody cetuximab with one of two tyrosine kinase inhibitors: gefitinib or erlotinib. "It looks like the impact of the drugs in combination will be synergistic," said Harari.



             
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