Unlocking the Combination for Treating Malignant Melanoma

A study in PLOS One suggests a novel combination of drugs that might be effective in treating malignant melanoma.

The finding is important because melanoma is among the deadliest cancers, and because despite the fact that a newer generation of anti-cancer drugs targeting underlying somatic genetic driver events result in significant response rates in some patients, many have incomplete responses to therapy. “Even among patients who do respond, most will develop acquired resistance within a year, often due to additional mutations or bypass pathways,” the researchers noted.

Combining anti-cancer drugs is a promising idea that rarely translates into clinical development, in part because of the sheer volume of drugs currently approved or in development. Testing each potential combination for its therapeutic effect in rigorous clinical trials is a task that straddles the line between difficult and impossible.

Researchers at the Massachusetts General Hospital (MGH) Center for Molecular Therapeutics tackled the problem by focusing screening on BRAF mutations, which are known to be the drivers in about half of all malignant melanoma cases.

This large-scale study utilized 36 well-characterized melanoma cell lines assembled by researchers at the Massachusetts General Hospital (MGH) Center for Molecular Therapeutics to test all possible combinations of more than 100 oncology drugs, two-thirds of which are currently in clinical use. The researchers tested a staggering number of combinations (nearly 6,000) looking for effects on the number and viability of tumor cells.

While promising evidence emerged for several combinations, the combination showing the most promise paired the BRAF inhibitor vemurafenib with cediranib, an investigational drug that targets the mitogen-activated protein kinase enzymes MEK1 and MEK2 that are often hyperactive in cancer cases. The researchers don’t yet know exactly why the particular combination is effective. Additional research will be needed to confirm the result and establish the mechanisms behind the combination’s success.

“We need to confirm this synergistic activity of vemurafenib and cediranib across a broader range of melanoma models, investigate why the particular combination is effective, and find biomarkers that predict which patients with BRAF-mutant melanoma should receive this combination,” said study leader Adam Friedman, MD, PhD, of the CBRC and the MGH Cancer Center, in a press release.

“What is really exciting is that these drugs are already in the clinic; in fact a clinical trial for a similar combination is already underway at another research center. We may be able to quickly improve on the selection criteria for this trial and identify patients whose tumors might respond.”

The melanoma arm was just one of several of the larger MGH study, which may prove influential beyond identifying promising combinations of melanoma therapies. The researchers hope that the study will ultimately provide a roadmap for how to use other large datasets to examine the potential of combinations across the oncology spectrum and beyond.