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

Chandrani Chattopadhyay; Janos Roszik; Rajat Bhattacharya; Md Alauddin; Iqbal Mahmud; Sirisha Yadugiri; Mir Mustafa Ali; Fatima S Khan; Varun Vijay Prabhu; Philip L Lorenzi; Bo Wei; Elizabeth Burton; Rohini R Morey; Rossana Lazcano; Michael A Davies; Sapna P Patel; Elizabeth A Grimm

doi:10.1038/s41416-024-02866-6

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

Br J Cancer. 2024 Oct 11. doi: 10.1038/s41416-024-02866-6. Online ahead of print.

Authors

Chandrani Chattopadhyay¹, Janos Roszik^{2

3}, Rajat Bhattacharya⁴, Md Alauddin², Iqbal Mahmud^{5

6}, Sirisha Yadugiri², Mir Mustafa Ali², Fatima S Khan², Varun Vijay Prabhu⁷, Philip L Lorenzi^{5

6}, Bo Wei^{5

6}, Elizabeth Burton³, Rohini R Morey⁸, Rossana Lazcano⁸, Michael A Davies^#², Sapna P Patel^#^{2

9}, Elizabeth A Grimm^#²

Affiliations

¹ Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA. cchattop@mdanderson.org.
² Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA.
³ Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA.
⁴ Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA.
⁵ Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA.
⁶ Metabolomics Core Facility, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA.
⁷ Chimerix, Durham, NC, 27713, USA.
⁸ Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA.
⁹ Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA.

^# Contributed equally.

PMID: 39394450
DOI: 10.1038/s41416-024-02866-6

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.