Online Extra: Different Drugs for Different Patients

Scientists are finding one magic bullet won't fight everyone's cancer. The answer: Individually tailored treatments

Lance Liotta and Emanuel F. Petricoin are convinced that they know how to tame cancer. The bad news is that getting there will be a long and expensive journey because virtually every patient will require a different treatment.

Liotta is chief of the pathology laboratory at the National Cancer Institute, and Petricoin is a microbiologist at the Food & Drug Administration. The two scientists are close collaborators on a new approach to fighting cancer. And they both believe that most current approaches -- even the much-hyped new molecularly targeted therapies -- are doomed to failure if used alone.

Why? "Cancer cells are normal cells that have gone crazy, like ordinary people who suddenly start killing their neighbors," explains Liotta. Almost every treatment strategy to date has been based on the idea that a cancer cell has something radically different, such as "a unique cancer-only protein that we can target with our drugs," as Liotta puts it.

"UNIQUE ENTITY."

  That assumption, he suspects, is wrong. Cancer cells aren't that different from regular cells. As a result, a magic bullet may never be found. What's more, the disease may take thousands of different forms -- each patient may have a different set of molecular defects. "We may have to think of each patient's cancer as a unique entity unto itself," says Petricoin.

This has tremendous implications for treatment. In the view of Liotta and Petricoin, only one viable approach can keep cancer in check. The first step is figuring out what specific pathways have gone haywire in a patient's tumor. Then, hit the deranged pathway with a targeted drug. But at the same time, doctors will also need to monitor the cancer to see how the abnormal cells react. When they inevitably mutate to shake off the drug's effect, doctors need to be ready to hit the cancer with a different drug or combination of drugs that target the new cellular circuitry. When the cancer adapts again, doctors will need yet another combination of drugs.

It may also be necessary to hit several of the deranged pathways at once. "One of the failures of cancer treatment is that it has focused only on one target. We think the whole pathway should be the target," says Liotta. "If we could just target two or three different parts of the pathway, we can change cancer treatment."

VARYING RESPONSES.

  To bring about this revolutionary change, Liotta and Petricoin are using new technologies to analyze the molecular differences between tumors and normal cells. In particular, they're analyzing the changes in types and levels of proteins in the cell, an approach called proteomics. "We're now able to get information that we never knew existed," says Petricoin.

For instance, Liotta and Petricoin are collaborating on a clinical trial at the National Institutes of Health for breast and ovarian cancer patients. The patients are getting a new targeted therapy, herceptin, along with a more traditional drug, taxol. As the patients are being treated, the two scientists are analyzing the changes in the tumors.

The results reveal why some patients respond to the treatment and others don't. The tumors have a protein, called AKT, that helps cancer cells survive. In some patients, herceptin deactivates this protein. That, in turn, makes the cells more vulnerable to taxol. As a result, the tumors shrink. But in other patients, herceptin doesn't deactivate AKT -- and taxol has no effect.

MORE EFFECTIVE.

  Scientists can now use these results to identify beforehand who will respond to this particular treatment. Those who won't respond, therefore, won't be forced to shoulder the double burden -- having cancer and being put through a debilitating treatment with little or no effect.

The two scientists also expect that the explosion of knowledge about cancer's molecular pathways will lead to a whole array of new drugs. True, they say, each drug would have a much smaller market than today's cancer treatments, since it will work only for a small set of cancers. But the flip side is that the drug -- or a combination of drugs -- will be far more effective. "If we tailor drug X, Y, or Z to patients, we'd have a much higher response rate," explains Petricoin.

This future is still years away. But as scientists uncover cancer's molecular secrets, they're beginning to understand how the disease could be held in check.

By John Carey in Washington

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