伊匹单抗抑制人葡萄膜黑素瘤原位肝转移小鼠模型的肿瘤生长并提高生存率。

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

机构信息

Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA.

Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA.

出版信息

Br J Cancer. 2024 Dec;131(11):1846-1857. doi: 10.1038/s41416-024-02866-6. Epub 2024 Oct 11.

DOI:10.1038/s41416-024-02866-6

PMID:39394450

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11589887/

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.

摘要

背景

葡萄膜黑色素瘤（UM）是一种侵袭性很强的疾病，治疗选择非常有限。我们之前的研究表明，mUM 的特征是高氧化磷酸化（OXPHOS）。在这里，我们测试了 imipridones 的抗肿瘤、信号和代谢作用，imipridones 是 CLPP 激活剂，可间接抑制 OXPHOS，并且在患者中表现出安全性。

方法

我们评估了 UM 患者样本中的 CLPP 表达。我们测试了 imipridones（ONC201 和 ONC212）对 UM 细胞系在体外的生长、存活、信号和代谢的影响，以及在 UM 肝转移模型中的体内治疗效果。

结果

CLPP 表达在原发性和 mUM 患者样本中检测到。ONC201 和 212 降低了 OXPHOS 效应物，抑制了人 UM 细胞系的细胞生长和迁移，并诱导了细胞凋亡。ONC212 抑制 OXPHOS，增加代谢应激和凋亡途径，抑制氨基酸代谢，并诱导与细胞死亡相关的脂质。ONC212 还降低了两种 UM 肝转移模型中的肿瘤负担并提高了存活率。