Targeting iron metabolism-dependent ferroptosis to trigger non canonical uveal melanoma death – IronMed

Metastatic uveal melanoma (mUM) is an aggressive and deadly neoplasm for which there is an urgent need for the identification of efficient therapeutic strategies to improve patient survival. One of the major genetic alterations observed in mUM associated with a poor prognosis is BAP1 loss which might induce a stem cell-like cellular phenotype. In numerous neoplasms, cancer cells with stem cell-like cellular phenotype (CSCs) can fuel tumor growth and plays an important role in the evolution of therapeutic resistance, tumor relapse and metastasis. This highlights an urgent need for the design of innovative treatment strategies aimed at exterminating CSCs with long-term growth and invasiveness properties.
Salinomycin and its derivatives have been shown in different cancers to alter iron metabolism and eliminate SCs through ferroptosis, which therapeutic interest in UM remains to be explored.
Of note, cancer genomic analyses using The Cancer Genome Atlas (TCGA) data sets based on BAP1-regulated genes have linked SLC7A11, a regulator of ferroptosis, to BAP1-mediated tumor suppression in different types of cancers.
Although, BAP1 deficiency is commonly observed in UM as discussed above, the link to iron metabolism, ferroptosis and “stemness” features has not yet been investigated. This prompted us to investigate whether targeting iron metabolism could be a therapeutic opportunity to fight BAP1-dependent “stemness” through modulation of ferroptosis.
This project aims to characterize the molecular basis of iron metabolism and ferroptosis upon salinomycin and its derivatives treatment and BAP1 role in these processes; to study the mechanisms by which BAP1, along with iron metabolism, regulates the CSC-like cellular phenotype in UM; and to test in vivo the impact on tumor growth of the compounds alone or in combination with candidates identified in previous axes.
The goal of this innovative project is to demonstrate that altering iron metabolism to induce ferroptosis is a promising therapeutic strategies for this difficult to treat disease, mUM.