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Sara Rezzola, Alessandra Loda, Arianna Giacomini, Roberto Ronca, Mohd Imtiaz Nawaz, Francesco Semeraro, Marco Presta; Cancer Stem-like Cells: a new therapeutic target for the treatment of metastatic uveal melanoma. Invest. Ophthalmol. Vis. Sci. 2020;61(7):3623.
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© ARVO (1962-2015); The Authors (2016-present)
Uveal melanoma (UM) is the most common primary intraocular malignancy in adults. Approximately 30% of UM patients die of their disease, usually because of hematogenous metastatic spread to the liver. Lack of approved drugs for the treatment of metastatic UM makes novel therapies eagerly required. In this frame, UM Cancer Stem-like Cells (CSC-like), a subpopulation resistant to chemotherapy and responsible for UM regrowth and dissemination, may represent a novel therapeutic target. TheFibroblast Growth Factor (FGF) system has been implicated in tumor progression and in the maintenance, regulationand survival of the CSC-like population in several human cancers. On this basis, we investigated the effect of the pan-FGF trap NSC12 on UM progression, focusing on the UM CSC-like subpopulation.
UM cell proliferation and apoptosis were evaluated by cytofluorimetric analysis. Gene expression was performed by qRT-PCR. Identification of the CSC-likepopulation was performed by ALDH FACS analysis and melanosphere formation capacity under non-adherent conditions. Activation of the autocrine FGF/FGF receptor (FGFR) axis was assessed by Western blotting.
Analysis of the Cancer Genome Atlas UM PanCancer Atlas dataset identifies FGFR or FGF overexpression in 21% and 61% of UM cases, respectively. These alterations were associated to reduced patient survival, chromosome 3 monosomy and BAP1 mutation. Accordingly, treatment of Mel285, Mel270, 92.1 and OMM2.3 UM cell lines with the anti-FGF NSC12 significantly impairs cell proliferation (IC50=6-8 µM). In addition, NSC12-treated Mel285 cells showed an increased cleavage of the pro-apoptotic Caspase 3 and PARP proteins followed by cell death.Notably, NSC12 treatment strongly affects the survival of the CSC-like ALDH+ population, which is more susceptible than ALDH- cells to its FGF-trap activity. Accordingly, pre-treatment with NSC12 significantly hampers the melanosphere formation capacity of UM cells. Finally, inhibition of the FGF/FGFR system induces a significant reduction of the expression of CSC-like-associated stemness and drug resistance-related genes.
Our data support the hypothesis that the FGF-trap NSC12 may act as a novel prodrug able to target the UM CSC-like subpopulation, thus representing an interesting option for the treatment of FGF/FGFR-driven UM.
This is a 2020 ARVO Annual Meeting abstract.
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