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May 30, 2006 • Volume 3 / Number 22 E-Mail This Document  |  Download PDF  |  Bulletin Archive/Search  |  Subscribe

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After Gleevec, Targeted Drugs Acquire More Targets

Targeted therapies were the big news last year at the American Society of Clinical Oncology (ASCO) annual meeting, where researchers presented results showing that many patients had benefited from drugs that interact with one particular molecule.

This year's meeting, which opens in Atlanta on Friday, will preview the next generation of targeted therapies, such as drugs for patients who cannot take the first-generation drugs and "multitargeted" drugs that interact with a small number of proteins rather than just one.

Like imatinib (Gleevec), trastuzumab (Herceptin), and other drugs created to hit a single target, the newer medicines are much less toxic than chemotherapy. And the hope is that by engaging more targets, these drugs will work when others do not and possibly against multiple cancers.

This idea was validated in January, when the Food and Drug Administration (FDA) issued its first dual approval for a drug. The agency approved sunitinib (Sutent) for kidney cancer and for gastrointestinal stromal tumors (GIST) when the primary treatment, imatinib, fails.

Sunitinib was designed to inhibit several proteins involved in two key aspects of cancer - cell growth and the formation of blood vessels that feed tumors, or angiogenesis.

"After starting with very nonspecific medicines such as chemotherapy, we're now going around a corner again toward more broadly targeted agents that hit multiple genetic pathways," says Dr. George Demetri of the Dana-Farber Cancer Institute, who led the clinical trials for sunitinib.

"The good news is that the more broadly targeted drugs may be applicable to different cancers, as we've seen with sunitinib," says Dr. Demetri.

In his research on GIST, Dr. Demetri has gone from being "laser focused" on a single protein to focusing on multiple pathways, or interactions, that involve many proteins inside the cell.

The good news is that the more broadly targeted drugs may be applicable to different cancers, as we've seen with sunitinib. - Dr. George Demetri

He points out that the word "targeted" has caused confusion, even among scientists, because all drugs have targets, including chemotherapy. But compared with chemotherapy, targeted drugs do a better job of killing only cancer cells.

Their stunning selectivity was first illustrated in the late 1990s, when researchers reported that imatinib could shut down a single mutant protein in patients with chronic myeloid leukemia (CML), often sending the disease into remission.

But imatinib stops working in some patients eventually, while others cannot tolerate the drug. Two medicines for these patients have been in clinical trials, and one of them, dasatinib, will be reviewed by an FDA drug advisory committee at ASCO on Friday.

Dasatinib targets nearly all the genetic mutations that cause resistance to imatinib and is "an important step forward," for many patients, says Dr. Neil Shah of the University of California, San Francisco, who will present findings from dasatinib trials at ASCO.

For some CML patients who do not tolerate imatinib, it can be devastating to learn that they cannot take "one of the great advances in cancer medicine," says Dr. Shah. But many of these individuals benefit from dasatinib, and "that's quite exciting."

ASCO will also feature results from trials involving another multitargeted drug, lapatinib (Tykerb). GlaxoSmithKline recently announced plans to seek FDA approval for lapatinib as a treatment for metastatic breast cancer.

Interest in multitargeted drugs is high right now in part because researchers are not as worried as they once were about side effects associated with less specific drugs, says Dr. Brian Druker of Oregon Health & Science University Cancer Institute, who led the development of imatinib.

"There's been a change in thinking," he says. It used to be that the more specific drugs were preferred in order to limit side effects. But clinical studies have shown that most targeted drugs are well tolerated, and today there are fewer concerns about toxicity.

"This is a complete turnaround in how people think about targeted therapies," he says.

Another factor driving interest in multitargeted drugs is economics. "Companies realize that if they can get away with a less specific drug, they might have a bigger market for it," says Dr. Druker.

Meanwhile, studies have suggested that some targeted drugs hit targets they were not intended to hit. Rather than seeing this as a design flaw, however, some view the ability to bind multiple proteins - a trait known as promiscuity - as an asset.

"Promiscuity can be a virtue," says Dr. Longgui Wang of the New York University School of Medicine, who has written about promiscuous drugs. "Cancers often have a number of abnormalities, and we have found that in these cases single-target drugs produce poor results."

Dr. Wang and others are now asking a question that will be explored in the years ahead: What is the best strategy for treating cancer - using multitargeted drugs or combining single-target drugs into "cocktails" like those used to treat HIV/AIDS?

The decisions will be made based on a mixture of efficacy, safety, tolerability, and even cost, says Dr. Demetri. He has programs testing a combination of three single-target inhibitors and others using promiscuous drugs designed to hit multiple pathways at once.

"We haven't made a decision yet, and in the end, we'll let the data speak for itself," he says.

By Edward R. Winstead