University of Colorado Anschutz Cancer Center researchers are making progress on finding better treatments for rare melanomas — melanomas that form not on the skin, but on non-sun exposed sites including mucous membranes in the head, neck, respiratory tract, and genitourinary region.
“These melanomas, which we call mucosal melanomas, tend to be extremely difficult to treat,” says cancer center member Martin McCarter, MD, professor of surgical oncology in the CU Anschutz School of Medicine. “They tend to be more advanced when they’re diagnosed, and they respond very poorly compared to standard cutaneous melanomas.”
Earlier in August, McCarter and cancer center member Kasey Couts, PhD, associate professor of medical oncology and co-director of the CU Center for Rare Melanomas, published the results of research conducted at the CU Anschutz Cancer Center that found that a medication called decitabine is effective in reversing the suppression of innate immune pathways in rare melanomas that are resistant to immunotherapy. That could open the door for immunotherapy drugs to come in and work more effectively.
“This research is the preclinical rationale that motivated us to try and get funding to launch a clinical trial of this drug combination,” Couts says. “Once we discovered that suppression of this intratumoral signaling pathway was associated with immunotherapy resistance in rare melanomas, we took patient tumor preclinical models and started treating them with drugs that have been previously reported to boost activity of this pathway. We identified decitabine, which is most commonly used to treat leukemias, as an effective drug to turn this pathway back on in our rare melanoma models.”
A phase I clinical trial of a new oral formulation of decitabine at the CU Anschutz Cancer Center, funded by a grant from the National Comprehensive Cancer Network, showed promise but enrolled only eight patients before being ended prematurely by the pharmaceutical company that manufactured the drug. Despite the trial’s low enrollment, correlative and translational analyses led by cancer center investigator Richard Tobin, PhD, provided valuable insight into the drug’s biological activity, showing that decitabine appeared to have the intended effect on the targeted immune signaling pathway.
“Two of the patients had a prolonged clinical benefit from the combination as a first-line treatment,” McCarter says. “The patients who had already been treated with other therapies did not do as well. But as a phase I study, there was enough data to suggest that firsts of all, the drug combination is tolerable with expected side effects, and second of all, the decitabine appeared to hit the intended immune signaling pathway. Although too small a sample size to evaluate clinical outcomes, some patients appeared to benefit. We hope to continue studying this pathway and see if we can improve on this effort.”
The research that Couts and McCarter conducted on decitabine and its effect on the immune pathway revealed another promising research direction: uveal melanoma, a type of eye cancer.
“In the future, we may launch a clinical trial for not just mucosal melanoma, but multiple different melanoma subtypes,” Couts says. “In the preclinical paper, we found that lower expression of this pathway was also a very common immunotherapy resistance mechanism in uveal melanoma. Low innate immune signaling actually appears to be a common resistance mechanism across all melanoma subtypes, and even in other cancers outside of melanoma. One of the things we’re working on in the lab is identifying biomarkers to help us identify which patients might benefit from the decitabine addition.”
As they plan for another clinical trial, Couts and McCarter are looking at other drugs that trigger the immune pathway besides decitabine.
“There are a few other approaches we're looking at to turn on this signaling pathway, including new drugs in development that activate this pathway through different mechanisms,” Couts says. “We want to get this information out there and share it with the broader cancer research community. We're all struggling with how to overcome immunotherapy resistance, and by us sharing our findings we hope it may help other researchers, and ultimately patients, as well.”