Researchers find possible drug targets for undruggable melanomas

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Researchers at Vanderbilt University have discovered promising drug targets for previously hard-to-treat types of melanoma, suggesting that some cancers believed not to have such targets actually do.

After screening tumor samples taken from patients, investigators found two novel BRAF protein fusions in melanomas that were previously thought to be devoid of molecular targets, making them unsuitable for certain cancer drugs. In some cancers, two or more genes mistakenly fuse together to produce abnormal proteins, or protein fusions, which can act as the drivers of those cancers.

A number of mutations in the genes BRAF, NRAS, KIT, GNAQ and GNA11 are known drivers for melanoma, the most dangerous type of skin cancer. But about 35% of melanomas, considered "pan-negative," do not have any of these known mutations.

Katherine Hutchinson, Vanderbilt Department of Cancer Biology doctoral candidate--Courtesy of Vanderbilt

The Vanderbilt team found that both newly discovered BRAF fusions activated a pathway in the cancer cells called the MAPK signaling pathway. Additional testing showed that a drug that inhibits a protein in the MAPK signaling pathway called MEK blocked the signaling induced by the BRAF fusions, suggesting that melanomas with these fusions could be treated with anticancer drugs that inhibit the MEK pathway. From their findings, the researchers conclude that up to 8% of so-called pan-negative melanomas could have this protein fusion. The findings were published in Clinical Cancer Research, a journal of the American Association for Cancer Research.

"If you think of melanoma as a pie, we're just chipping away at a piece of the pie," Katherine Hutchinson, first author of the study and a Vanderbilt Department of Cancer Biology doctoral candidate, told FierceBiotechResearch in an interview.

Dr. Jeffrey Sosman, professor of medicine at Vanderbilt-Ingram Cancer Center--Courtesy of Vanderbilt

Until recently, pan-negative patients could only be treated with radiation and chemotherapy, and some could undergo surgery. "Patients who are pan-negative are ineligible for any of the targeted agents that are out there," Hutchinson said.

Hutchinson said she is already searching for the next target for pan-negative melanoma, and her team is studying patients that may have unexplained--both good and bad--responses to cancer drugs.

"Currently, there is immense value in identifying novel mutations in untreatable cancers because many of them are clinically relevant, which means they may be sensitive to drugs that are either being developed or are already FDA approved," Dr. Jeffrey Sosman, a professor of medicine at Vanderbilt-Ingram Cancer Center, said in a statement. "Our data support the idea that 'pan-negative' cancers are not truly pan-negative."

- read the press release
- see the study abstract

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