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Skin Health

A Milestone in Understanding Treatment-Resistant Melanoma

Within the past few years, new treatments have begun to turn the tide against metastatic melanoma, improving and even saving the lives of countless people with this deadly disease.

One of the new treatments, mutation-targeted therapy, disrupts the effects of a genetic mutation that occurs in half of all people with metastatic melanoma, according to a three-year study led by Dr. Roger Lo, a member of the UCLA Jonsson Comprehensive Cancer Center and published online by the journal Cell on September 10th 2015. Although the therapy has been promising, an ongoing challenge is that, for many patients, the cancer may become resistant to the treatment after several months or years. When that happens, the cancer recurs, often in a more aggressive form than the original melanoma.

A release from UCLA states that the study could mark a milestone in the quest to track how cancer changes in response to a powerful drug. The findings, Lo said, could lead to methods that would enable early detection of drug-resistant tumor cells and to new therapies designed to suppress resistance as soon as therapy begins.

Lo and his team investigated how metastatic melanoma evolves to become more malignant and resistant to treatment. The cancer mutation being targeted by the therapy occurs in a gene called BRAF. Mutations in the BRAF gene turn on a major cancer growth switch called MAP kinase pathway.

Collaborating with physicians from Vanderbilt–Ingram Cancer Center, Lo studied drug resistance by analyzing samples of patients’ melanoma tumors both before they underwent therapy and when the disease recurred. The scientists also replicated the process outside of the human body — modeling drug resistance by growing melanoma cell lines from patients’ tumors and adapting them to drugs that block the MAP kinase pathway.

The researchers realized early during their work that they could not fully explain the way tumors change behavior after patients begin therapy by analyzing gene mutations alone. So they used two techniques: genomics (which allows numerous gene mutations to be detected in parallel) and epigenomics (which detects all of the changes in the genes’ activities inside the tumors).

Scientists now know that immune cells directly inside the tumors play key roles in controlling the growth of the cancer cells, thanks to the development of life-saving immunotherapies within the past few years.

“Only cancer cells, not immune cells inside the tumors, accumulate gene mutations,” said Lo, who is also an associate professor of dermatology. “Mutational profiling alone cannot tell us about the state of the intratumoral immune cells and their changing states when melanoma becomes resistant to therapy.”

The researchers gained insights about the immune cells that entered the patients’ tumors by tracking the levels of gene activities.