Faculty, Staff and Student Publications
Publication Date
12-1-2024
Journal
British Journal of Cancer
Abstract
Background: Uveal 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, which are CLPP activators, which inhibit OXPHOS indirectly and have demonstrated safety in patients.
Methods: We assessed CLPP expression in UM patient samples. We tested the effects of imipridones (ONC201 and ONC212) on the growth, survival, signaling and metabolism of UM cell lines in vitro, and for therapeutic efficacy in vivo in UM liver metastasis models.
Results: CLPP expression was detected in primary and mUM patient samples. ONC201 and 212 decreased OXPHOS effectors, inhibited cell growth and migration, and induced apoptosis in human UM cell lines in vitro. ONC212 inhibited OXPHOS, increased metabolic stress and apoptotic pathways, inhibited amino acid metabolism, and induced cell death-related lipids. ONC212 also decreased tumor burden and increased survival in vivo in two UM liver metastasis models.
Conclusions: Imipridones are a promising strategy for further testing and development in mUM.
Keywords
Uveal Neoplasms, Animals, Melanoma, Humans, Mice, Liver Neoplasms, Cell Line, Tumor, Cell Proliferation, Apoptosis, Xenograft Model Antitumor Assays, Oxidative Phosphorylation, Disease Models, Animal, Female, Imidazoles, Uveal Melanoma
DOI
10.1038/s41416-024-02866-6
PMID
39394450
PMCID
PMC11589887
PubMedCentral® Posted Date
10-11-2024
PubMedCentral® Full Text Version
Post-print
Published Open-Access
yes
Included in
Bioinformatics Commons, Biomedical Informatics Commons, Genetic Phenomena Commons, Medical Genetics Commons, Oncology Commons