TREATING UVEAL MELANOMA

Uveal melanoma in particular, is notoriously difficult to treat once it has metastasized and grown in a distant organ. A remarkable new study suggests a potential role for histone deacetylase (HDAC) inhibitors for reducing the rates of metastasis seen with this cancer. The drugs (Valproate et al.), normally used to treat seizures, alter the conformation of the DNA of the aggressive form of uveal melanoma, which changes the way key genes are expressed, rendering the tumour cells less aggressive. Specifically, researchers built on previous research showing that a mutation in a gene called BAP-1 helped explain why some uveal tumours develop the class 2 signature associated with high risk for metastasis. The HDAC inhibitors appear to reverse some of the effects of BAP-1 mutations on the melanoma cell. Working in vitro, the researchers evaluated various compounds for their effects on uveal melanoma cells using morphologic evaluation, MTS viability assays, BrdU incorporation, flow cytometry, clonogenic assays, gene expression profiling, histone acetylation and ubiquitination assays. They also used an in vivo murine xenograft tumorigenicity model. The HDAC inhibitors induced morphologic differentiation, cell cycle exit, and a shift to a differentiated, melanocytic gene expression profile in cultured cancer cells. Valproic acid in particular inhibited the growth of uveal melanoma tumours in vivo. Because HDAC inhibitors already are on the market, the investigators believe it may be possible to begin testing the drugs in patients with aggressive forms of uveal melanoma within 12 months. Valproate and drugs in its class have relatively mild side effects that are not as severe as those seen in patients undergoing conventional chemotherapy. The most common side effect is drowsiness. The researchers believe the likely role for HDAC inhibitors will be to slow or prevent the growth of tumour cells that have spread out of the eye but cannot yet be detected. This might lengthen the time between the original eye treatment and the appearance of detectable cancer in the liver and elsewhere. This would allow patients with aggressive melanomas to live for many years without any detectable spread of
their disease.

S Landreville et al., Clinical Cancer Research, “Histone dacetylase inhibitors induce growth arrest and differentiation in uveal melanomaâ€, doi:10.1158/1078-0432.CCR-11-0946.