Researchers, led by scientists at Memorial Sloan-Kettering Cancer Center, have discovered that a new class of drugs -- now in early stage clinical trials -- work best in patients with mutations in the BRAF gene.

BRAF is a protein that plays a central role in the growth and survival of cancer cells and is mutated in the majority of patients with melanoma and in a minority of patients with colon, breast, and lung cancers.

The findings, published in the Nature, represent a potential targeted therapy tailored for patients whose tumors contain this mutation.

The researchers found that drugs that inhibit a protein called MEK selectively inhibited the growth of cancer cells lines and tumors that have a mutated BRAF gene.

One of these drugs, PD0325901, developed by Pfizer, is now being tested in clinical trials of patients with melanoma, colon, breast, and lung cancers.

In addition, by re-analyzing the data on more than 42,000 compounds tested by the National Cancer Institute against a panel of 60 cancer cell lines, the investigators were able to identify a small number of other compounds that also selectively inhibit tumors that have the BRAF mutation. While the mechanism of action of some of these compounds has yet to be determined, several of the most effective compounds were also inhibitors of the MEK protein.

" We find that all tumors with the BRAF mutation and some with the RAS mutation are sensitive to drugs that inhibit MEK," explained Neal Rosen, at Memorial Sloan-Kettering and the study's senior author. " Translating these findings into a strategy for treating patients whose tumors are dependent upon this specific genetic change is the next step, and such clinical trials are now ongoing."

" The BRAF mutation was first identified by a consortium of investigators searching for proteins that are frequently mutated in human cancer," said David Solit, the study's first author and at Memorial Sloan-Kettering who is also a member of Rosen's laboratory.

This project, an outgrowth of the Human Genome Project, called the Cancer Genome Project, has the goal of identifying the causative mutations that cause human cancers.

Source: Memorial Sloan-Kettering Cancer Center, 2005


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