The promise of a new treatment for deadly, late-stage melanoma — heralded by the finding that 80 percent of otherwise-untreatable patients saw their tumors shrink in early trial results published in August — has now been marred by disappointment. Patients who have been on the treatment for seven to nine months are seeing their cancer relapse.
But in two studies to be published tomorrow (Nov. 25) in the journal Nature, researchers report they have begun to uncover the cellular changes causing tumors to become resistant to the drug, called PLX4032, and that understanding these changes points the way to developing further treatments for the disease.
“In melanoma as well as several other cancers, there is a critical need to understand resistance mechanisms, which will enable us to be smarter up front in designing drugs that can yield more lasting clinical responses,” said Dr. Levi Garraway, an author of one of the studies and a medical oncologist at Dana-Farber Cancer Institute in Boston.
One of the studies found that melanomas develop resistance to PLX4032 in a seldom-seen way in the world of cancer.
“Lots of people were expecting a common mechanism of resistance,” said study researcher Dr. Roger Lo, of the University of California, Los Angeles Jonsson Comprehensive Cancer Center. “But what we found was a big surprise,” he said.
Most cancers, Lo explained, become resistant to the drug treatments when they develop what scientists call a secondary mutation. In 50 to 60 percent of patients with melanoma, the cancer itself is brought on by a mutation in a gene called B-RAF — and it's B-RAF that the drug PLX4032 targets. So scientists expected to find that a “second” mutation in B-RAF was letting the cancer cells outwit the drug and leading to resistance.
But the researchers found that melanoma cancers develop resistance to PLX4032 in other ways. Some develop a mutation in another gene that turns on the same pathway B-RAF turns on — basically “short-circuiting” the effect of the drug, Lo said. This gene could be targeted with another treatment, and in fact, drugs that target this gene are already in development or being used to treat other types of cancers.
Other melanomas survive in the face of PLX4032 treatment by setting up a new pathway altogether, which lets them grow even though B-RAF has been shut down. For patients with this type of resistance, an experimental group of drugs called m-Tor inhibitors could possibly be used as treatments, Lo said.
Garraway's study showed yet another mechanism of resistance. A protein called COT — which had not previously been shown to be at work in human cancers — was found in elevated levels in drug-resistant tumor cells in lab dishes. And the researchers found that in two of the three tumor samples they examined from patients who had relapsed after treatment, levels of COT were raised.
The next logical step in the research, Lo said, would be to find how treatments might be combined for each patient. And it's likely that still other mechanisms of resistance have yet to be uncovered, both researchers said. For example, in their work, Lo and his colleagues used samples of melanoma tumors from 12 patients, and their discoveries explain five of those cases of resistance.
But the findings also signal a larger change in the way cancer treatments are approached, Lo told MyHealthNewsDaily.
In treating many types of cancer, physicians take a “sequential” approach to drug-resistant tumors: they treat patients with one drug until the cancer cells seem to no longer respond to the drug, and then begin treatment with a second drug designed to treat the drug-resistant tumor.
But eventually, the options run out. The National Cancer Institute estimates that 8,700 people will die of melanoma of the skin in 2010.
“The more we find out about the mechanisms of resistance… we're seeing we need to take a global view of the converging events in cancer, which could all be targeted at the start,” Lo said. This type of “combinatorial” approach would involve treating patients with several drugs at the outset.
“It may make more sense to give a cocktail to cover all types of resistance, not knowing which path of resistance a tumor is going to go down,” he said.
For now, the path leading to that future is being laid by trials of individual drugs, he said. “You have to show that individual agents work before combining them. We'll have more drugs at our disposal, then combining them will be the whole next generation of clinical trials.”
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