Progress against melanoma

Stem cell researchers at Children’s Hospital Boston (CHB) have taken two important steps toward the development of a new way of treating melanoma, the most virulent form of skin cancer.

In two letters featured on the cover of the March 24 edition of the journal Nature, the researchers, led by HSCI Executive Committee chair Leonard Zon, MD, report isolating a gene that hastens the growth of melanoma tumors, and using an already approved drug, in combination with a drug now working its way through the federal Food and Drug Administration (FDA) approval process, to uncover new potential therapeutic targets in melanoma. Zon is also a professor in Harvard University’s Department of Stem Cell and Regenerative Biology and heads CHB’s stem cell program.

Zon said his group is now waiting for FDA approval of a drug that blocks the function of the gene BRAF, which has long been known as a melanoma promoter. “We’re planning on starting clinical trials at Massachusetts General Hospital and Dana-Farber Cancer Institute within six months of that approval,” he said.

The path toward the new findings began in 2005 with the development in Zon’s lab of a zebrafish model of human melanoma, Zon said. It was further accelerated, said Richard White, PhD, lead author of the paper and a postdoctoral fellow in Zon’s lab, by researchers’ use of novel genetic and chemical approaches — including drugs already approved for other purposes — that are uniquely available in the zebrafish system.

In the White letter, the researchers report that early in melanoma development, the BRAF gene causes the cells to become more “progenitor”-like, resembling a type of embryonic cell called neural crest stem cells.

“We asked what happens in the early stages of melanoma to the cells that acquire BRAF mutation,” White said. “We figured out that one of the things BRAF does is cause the animal to have too many embryonic-like neural crest cells. So we developed a chemical screen to find molecules that would suppress neural crest cells.”

The researchers screened a library of 2,000 chemicals in zebrafish embryos to find ones that eliminated these neural crest cells. “We look for drugs that are used for something else, and ask whether they can then be used” for the disease being studied, White said. The advantage of this strategy is that if a compound that is already FDA approved is found to be effective in initial studies it can be moved directly to human trials. In this case, the chemical, called lefunomide, was previously approved for treating rheumatoid arthritis.

By combining lefunomide with a drug awaiting FDA approval that blocks the BRAF gene, researchers magnify the effect of two drugs that, administered alone, have a smaller effect. Together, said White, the drugs completely knocked out melanoma in several human cell tests, and reduced tumor size in melanoma cells transplanted into mice as well.