Imipridones inhibit tumor growth and improve survival in an orthotopic liver metastasis mouse model of human uveal melanoma

Abstract

AbstractPurposeUveal melanoma (UM) is a highly aggressive disease with very few treatment options. We previously demonstrated that mUM is characterized by high oxidative phosphorylation (OXPHOS). Here we tested the anti-tumor, signaling and metabolic effects of imipridones, CLPP activators which reduce OXPHOS indirectly and have demonstrated safety in patients.Experimental DesignWe assessed CLPP expression in UM patient samples. We tested the effects of imipridones (ONC201, ONC212) on the growth, survival, signaling and metabolism of UM cell linesin vitro,and for therapeutic effectsin vivoin UM liver metastasis models.ResultsCLPP expression was confirmed in primary and mUM patient samples. ONC201/212 treatment of UM cell linesin vitrodecreased OXPHOS effectors, inhibited cell growth and migration, and induced apoptosis. ONC212 increased metabolic stress and apoptotic pathways, inhibited amino acid metabolism, and induced cell death-related lipids. ONC212 also decreased tumor burden and increased survivalin vivoin two UM liver metastasis models.ConclusionImipridones are a promising strategy for further testing and development in mUM.