Ulveal melanoma is a rare and aggressive type of melanoma that targets the eye and affects an estimated 2,500 people in the United States annually. Nearly half of these diagnoses will go on to develop metastatic uveal melanoma that will target other parts of the body—mainly the liver. Prognosis is often poor with a median survival of 17 to 20 months. However, researchers have now identified a drug combination designed to target the metastatic uveal melanoma cells in preclinical studies
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Researchers have designed uveal melanoma cell lines that were resistant to MEK inhibitors—drugs that target the MEK protein implicated in MAPK signaling of melanoma patients—and performed proteomic analysis to examine what signaling pathways were activated during the MEK inhibitor resistance process.
“We identified a number of putative escape pathways that were upregulated following MEK inhibition, including the PI3K/AKT pathway, ROR1/2 and IGF-1R signaling,” explained Keiran Smalley, PhD, director of Moffitt’s Donald A. Adam Melanoma and Skin Cancer Center of Excellence.
Researchers were hopeful that through the identification of critical signaling pathways, they can understand how uveal melanoma cells become resistant to treatment and then counteract with an additional drug alongside MEK inhibitors.
Findings were published in Clinical Cancer Research and reveal that histone deacetylase (HDAC) inhibitors drugs, particularly panobinostat, were most effective in targeting two critical pathways in the resistance process: AKT and YAP signaling.
“Our finding that a clinically approved pan-HDAC inhibitor was effective at simultaneously limiting YAP and AKT signaling in uveal melanoma cells suggests this could be a good candidate for future clinical development,” explained Smalley.
In mouse studies, these results indicate a successful combination treatment with HDAC panobinostat along with and the MEK inhibitor trametinib is effective at uveal melanoma tumor growth reduction.
Source: Moffitt Cancer Center
