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Targeted Therapies Aim for Cancer's Achilles Heel

Article date: June 15, 2006

Every night before bed, retired school teacher Paul Graves takes 4 pills that help keep him alive. The medication is Gleevec (imatinib), and it has kept Graves' chronic myeloid leukemia in remission for 4 years with virtually no side effects.

"I say, 'This is my surgery, this is my radiation, this is my chemotherapy,'" said Graves, who turns 67 next month. "It's absolutely amazing when you think of people losing their hair and losing body parts—it's a miracle drug."

Graves is living the promise of so-called targeted therapy, a new approach to taming cancer. Its goal: to kill cancer cells while leaving healthy cells relatively unharmed. Gleevec is just one of a slew of targeted therapy drugs being developed to tackle some of the most difficult and deadly cancers.

Targeted therapy is "one of the most exciting new themes in cancer therapy," according to José Baselga, MD, chief of the medical oncology service and director of medical oncology, hematology, and radiation oncology at Barcelona's Vall d'Hebron University Hospital. Baselga discussed advances in the field at the recent meeting of the American Society of Clinical Oncology (ASCO) in Atlanta.

Blocking Critical Pathways

Targeted therapy is based on knowledge of how cells grow, develop, and interact with each other. Researchers have discovered dozens of signaling pathways in cells that tell them whether to grow or not. Cancer cells often have abnormalities in these pathways, which cause them to grow out of control. Drugs that block these signals could help stop cancer in its tracks.

That's how many of today's targeted therapies work. Gleevec, for instance, blocks a protein that makes some abnormal white blood cells grow. The breast cancer drug Herceptin (trastuzumab) latches on to cancer cells that have receptors for the HER2/neu protein and keeps them from dividing and growing. Tarceva (erlotinib), which is used for lung cancer, blocks another protein the cells need to grow, EGFR.

Although each of these drugs can be effective, some cancers never respond to treatment, or they eventually become resistant to treatment. That has led researchers to explore ways of combining different targeted drugs to deliver a deadlier blow.

"Cancer cells are not as resourceful as you would think," explained Baselga. "If you can hit them in 2 critical pathways, you can destroy them, so if you can combine 2 or 3 therapies, you can cause profound cell death."

He calls this the "Achilles heel" of cancer.

Unlike cancer cells, most normal cells can tolerate blows to several signaling pathways; that's why these targeted drugs have fewer side effects than traditional chemotherapy.

Searching for the Most Effective Strategy

The question many researchers now wrestle with is, What's the best way to use different targeted therapies? Should they be given along with chemotherapy, or are they better by themselves? Should they be given in sequence, with a patient starting a second drug only after failing a first? Or would it be better (and still safe) to give 2 or 3 drugs at once?

Little research has been done using multiple targeted therapies at once. But recent studies presented at the ASCO conference show that giving drugs in sequence can have an effect.

The investigational drug lapatinib (Tykerb), for instance, seems to work for some women whose breast cancer no longer responds to Herceptin. In fact, the drugs appear to have complementary action. While Herceptin targets the part of the HER2 receptors on the outside of cells, lapatinib hits the part of the receptors inside the cells. That double whammy may be more effective than either drug alone, said Charles Geyer, MD, of Allegheny General Hospital in Pittsburgh, one of the researchers investigating lapatinib. Studies are now under way to see if this is indeed the case.

Likewise, the investigational drug dasatinib (Sprycel) seems to work for many people with chronic myeloid leukemia whose cancer no longer responds to Gleevec , or who can't take it for other reasons. That's good news for such patients, said Brian Druker, MD, professor of medicine at Oregon Health and Science University and one of the creators of Gleevec.

"If you look at the data overall, 18% of patients [on Gleevec] have some progression event at 5 years, and another 5% discontinue because of side effects," he explained. "So about 23% of patients need something else, so it's great to have dasatinib for them."

Neither lapatinib nor dasatinib are available outside of clinical trials in the US because they have not yet been approved by the Food and Drug Administration.

Chemotherapy Still Has a Place

Although these new drugs are very promising, experts caution that there's still a lot to learn about how targeted therapies work, and what their side effects would be if combined.

While some patients, like Paul Graves, do not experience bad effects from targeted therapies, others aren't as lucky. Some of these drugs can cause acne-like rashes that may be quite severe, diarrhea, or even heart problems. Would such effects be amplified if a patient took more than 1 drug at a time?

Cost is also a factor. Targeted therapies are very expensive and many patients cannot afford them. That's particularly true of people without health insurance.

All of that means chemotherapy isn't going the way of the dinosaurs just yet.

"Chemotherapy works," said Baselga, "and we're not in a situation where we can give up any efficacious therapy. One day we will be able to give up chemotherapy, but we're not there yet."

Still, most oncologists aren't waiting for big advances from chemotherapy treatments, said Len Lichtenfeld, MD, deputy chief medical officer for the American Cancer Society.

"Last year at ASCO we reached what I called a watershed moment where it was clear that targeted therapies were valuable, were having a significant impact on patient care, and were basically here to stay," he said. "The progress in this arena has been truly astounding and it is exciting to anticipate how much more we are going to learn in the near future."

Reviewed by: Members of the ACS Medical Content Staff

ACS News Center stories are provided as a source of cancer-related news and are not intended to be used as press releases.

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