TY - JOUR
T1 - Imipridones inhibit tumor growth and improve survival in an orthotopic liver metastasis mouse model of human uveal melanoma
AU - Chattopadhyay, Chandrani
AU - Roszik, Janos
AU - Bhattacharya, Rajat
AU - Alauddin, Md
AU - Mahmud, Iqbal
AU - Yadugiri, Sirisha
AU - Ali, Mir Mustafa
AU - Khan, Fatima S.
AU - Prabhu, Varun Vijay
AU - Lorenzi, Philip L.
AU - Wei, Bo
AU - Burton, Elizabeth
AU - Morey, Rohini R.
AU - Lazcano, Rossana
AU - Davies, Michael A.
AU - Patel, Sapna P.
AU - Grimm, Elizabeth A.
N1 - Publisher Copyright:
© The Author(s) 2024.
PY - 2024/12/14
Y1 - 2024/12/14
N2 - 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.
AB - 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.
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U2 - 10.1038/s41416-024-02866-6
DO - 10.1038/s41416-024-02866-6
M3 - Article
C2 - 39394450
AN - SCOPUS:85206652149
SN - 0007-0920
VL - 131
SP - 1846
EP - 1857
JO - British journal of cancer
JF - British journal of cancer
IS - 11
ER -