Melanoma: Finding the One-Two Punch that Works

A test of combinations of hundreds of agents, including statins, on metastatic melanoma cells found a number of combinations that showed promise.

A test of combinations of hundreds of agents, including statins, on metastatic melanoma cells found a number of combinations that showed promise.

A number of combination therapies that show promise in inhibiting melanomas associated with RAS and BRAF genetic mutations have been discovered by researchers at Yale Cancer Center. The drug combinations, including some that feature statins, were tested on cell lines drawn from metastasized melanomas. The researchers published their results online on December 13, 2012, in Cancer Discovery.

“Many melanoma patients have been greatly helped by identification of gene mutations that drive subsets of the disease,” said study co-author David F. Stern, PhD, professor of pathology at Yale School of Medicine, in a press release. “But even when they respond to initial single-drug treatment, most eventually become resistant to the drug, and their cancers return.”

Melanomas caused by RAS and BRAF mutations are among the most aggressive skin cancers, frequently exhibiting a partial response or outright resistance to therapy. BRAF mutations are linked to half of all melanoma cases, and RAS mutations occur in about 20% of melanoma patients. While a few current therapies for melanoma target the BRAF gene (eg, vemurafenib), initial success tends to be followed by the development of resistance and recurrence within months.

The researchers looked at the effects of combinations of 150 small molecule compounds on the metastatic melanoma cells, searching for those that successfully inhibited cell growth. Combinations are usually more effective than single agents, as they can inhibit multiple processes that sustain the cancer’s growth. In addition, 1 agent can inhibit growth while the other accelerates programmed cell death.

The researchers identified several previously unknown and unexplored combinations that effectively inhibited growth and promoted cell death in the melanoma cell cultures. Some offer promise in treating vemurafenib-resistant melanomas. Of particular interest is the finding that combining statins with drugs that inhibit enzymes involved in regulating and promoting cancer cell growth produced a similar response in melanoma cells driven by both RAS and BRAF mutations.

These results could direct attention to human trials using identified combinations. They are particularly promising because up to 30% of aggressive cancers are driven by RAS mutations, and RAS proteins lack major surface features susceptible to binding by drugs.

Ms. Wick is a visiting professor at the University of Connecticut School of Pharmacy and a freelance writer from Virginia.

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