Abstract
Simple SummaryUveal melanoma (UM) is the most common adult eye cancer. UM originates in the iris, ciliary body or choroid (collectively known as the uvea), in the middle layer of the eye. This first or primary UM is treated by targeting cancer cells using ocular radiation implants or by surgical removal of the eye. However, when UM spreads to the liver and other parts of the body, patients have a poor survival prognosis. Unfortunately, there are no effective treatment options for UM that has spread. Our aim is to help identify effective treatments for UM. In our study, we identified that the drug ACY-1215 prevents the growth of cells derived from UM in the eye and a UM that spread to the liver. Our pre-clinical study uncovered a potential treatment approach for advanced UM.Metastatic uveal melanoma (MUM) is characterized by poor patient survival. Unfortunately, current treatment options demonstrate limited benefits. In this study, we evaluate the efficacy of ACY-1215, a histone deacetylase inhibitor (HDACi), to attenuate growth of primary ocular UM cell lines and, in particular, a liver MUM cell line in vitro and in vivo, and elucidate the underlying molecular mechanisms. A significant (p = 0.0001) dose-dependent reduction in surviving clones of the primary ocular UM cells, Mel270, was observed upon treatment with increasing doses of ACY-1215. Treatment of OMM2.5 MUM cells with ACY-1215 resulted in a significant (p = 0.0001), dose-dependent reduction in cell survival and proliferation in vitro, and in vivo attenuation of primary OMM2.5 xenografts in zebrafish larvae. Furthermore, flow cytometry revealed that ACY-1215 significantly arrested the OMM2.5 cell cycle in S phase (p = 0.0001) following 24 h of treatment, and significant apoptosis was triggered in a time- and dose-dependent manner (p < 0.0001). Additionally, ACY-1215 treatment resulted in a significant reduction in OMM2.5 p-ERK expression levels. Through proteome profiling, the attenuation of the microphthalmia-associated transcription factor (MITF) signaling pathway was linked to the observed anti-cancer effects of ACY-1215. In agreement, pharmacological inhibition of MITF signaling with ML329 significantly reduced OMM2.5 cell survival and viability in vitro (p = 0.0001) and reduced OMM2.5 cells in vivo (p = 0.0006). Our findings provide evidence that ACY-1215 and ML329 are efficacious against growth and survival of OMM2.5 MUM cells.
Highlights
Uveal melanoma (UM) is the most common adult intraocular cancer, afflicting approximately 4.3 per million people worldwide [1]
Three commercially available histone deacetylase 6 inhibitors (HDAC6i) (Tubastatin A, ACY-1215 and Tubacin) were selected to determine their efficacy in reducing long-term proliferation of human UM cell lines derived from primary ocular UM (Mel285 and Mel270) and a metastatic liver (OMM2.5) UM [35,36,37]
Initial screens with 10–50 μM showed a dose-dependent reduction in UM cell proliferation of both primary UM cell lines and the metastatic UM cell line with all three HDAC6i tested (Figure S1)
Summary
Uveal melanoma (UM) is the most common adult intraocular cancer, afflicting approximately 4.3 per million people worldwide [1]. The most effective treatments for primary UM include surgical resection of the tumor, radiotherapy (plaque brachytherapy or proton beam therapy) and enucleation of the affected eye [4,6]. Approximately 50% of patients diagnosed with primary UM progress to develop metastatic UM (MUM), primarily in the liver (~89%), which is associated with poor survival prognosis (median overall survival (OS) ranging from 4 to 15 months) [2,7,8]. MUM patients receive site -directed therapies (including surgical resection of tumor), the chemotherapeutic drug Dacarbazine (commonly used to treat cutaneous melanoma) or immunotherapy drugs, such as Ipilimumab and Pembrolizumab [8,9]. There is still an imperative to identify highly efficacious, sustained treatments for MUM patients, as Tebentafusp has only been trialed in a subset of MUM patient cohort who are HLA-A*02:01-positive
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