Studies show how skin cancer evades promising drug

Wed Nov 24, 2010 1:00pm EST

* Findings could lead to cocktail of drugs for melanoma

* Teams hope to make melanoma a chronic disease

By Julie Steenhuysen

CHICAGO, Nov 24 (Reuters) - U.S. researchers have uncovered several ways in which melanoma can outsmart a promising experimental cancer pill called PLX4032, a finding that could lead to new drugs to keep the deadly skin cancer at bay, the teams said on Wednesday.

Researchers at the University of California, Los Angeles discovered two different resistance mechanisms that explain how melanoma stops responding to treatment with PLX4032, and a separate team at the Broad Institute of Massachusetts Institute of Technology and Harvard in Cambridge, Massachusetts, discovered a third.

They said the findings may lead to drug cocktails that could extend the effectiveness of PLX4032, a drug being co-developed by privately held biotechnology company Plexxikon and Roche (ROG.VX).

Up to 80 percent of patients with a genetic mutation in the BRAF gene respond to PLX4032, but the effect lasts only seven to nine months for most patients.

"The question is, when these patients relapse, 'What happens?'" said Dr. Roger Lo of UCLA, who worked on one the two studies published on Wednesday in the journal Nature.

Lo and colleagues at UCLA have been studying changes in cancer tumors taken from patients before and after treatment with PLX4032. The hope is to pin down exactly how the cancer is outsmarting the medication, Lo said in a telephone interview.

PLX4032 belongs to a new class of drugs that target tumor cells with a mutation in a gene called BRAF. The mutations occur in 50 percent to 60 percent of melanoma patients.

Lo's team initially suspected the cancer was developing additional BRAF mutations to get around the drug because that is how many cancers elude targeted drugs.

"You hit it with an axe, but the cancer soon finds a way to mitigate the effects of the axe," Lo said in a statement.

The team found no secondary mutations.

Instead, they found that in some patients, the cancer acquired resistance to PLX4032 by making too much of a protein on the outside of cancer cells that allowed it to survive. In another, they found mutations in a gene called NRAS that allowed the cancer to short-circuit the BRAF mutation, making the drug obsolete.

"We have 16 resistant tumors studied in this work. They come from 12 separate patients from both Phase I and Phase II trials. What we find is there are distinct mechanisms that offer different types of escape," Lo said.

He said the two mechanisms they discovered account for about 40 percent of the cases of resistance studied by the team, and he thinks there will be several more.

In a separate study, a team led by Levi Garraway and colleagues of the Dana-Farber Cancer Institute and the Broad Institute of Harvard and MIT found that in some patients treated with PLX4032, a cancer gene called COT -- also known as MAP3K8 -- drives resistance.

They found elevated levels of a protein made by the COT gene in samples from three patients with advanced melanoma who were treated with the drug PLX4032.

"We have no doubt that other resistance mechanisms are also going to be important in B-RAF mutant melanoma, but by taking a systematic approach, we should be able to find them," Garraway said in a statement.

Lo said many of the survival pathways used by the cancer can be attacked with existing cancer drugs or drugs that are being studied in clinical trials.

By tracking these down, he thinks, researchers will be able to develop a cocktail of drugs that will attack the cancer and cut off its escape routes, turning the most deadly of skin cancers into a chronic disease, much like drug cocktails have done for the treatment of AIDS.

Plexxikon and Roche are enrolling patients in a Phase III clinical trial of the drug, which is typically the final stage of human testing before a new drug is submitted to regulators for an approval decision. (Editing by Mohammad Zargham)

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