Back to Search
Start Over
Exploiting a subtype-specific mitochondrial vulnerability for successful treatment of colorectal peritoneal metastases.
- Source :
-
Cell reports. Medicine [Cell Rep Med] 2024 May 21; Vol. 5 (5), pp. 101523. Date of Electronic Publication: 2024 Apr 25. - Publication Year :
- 2024
-
Abstract
- Peritoneal metastases (PMs) from colorectal cancer (CRC) respond poorly to treatment and are associated with unfavorable prognosis. For example, the addition of hyperthermic intraperitoneal chemotherapy (HIPEC) to cytoreductive surgery in resectable patients shows limited benefit, and novel treatments are urgently needed. The majority of CRC-PMs represent the CMS4 molecular subtype of CRC, and here we queried the vulnerabilities of this subtype in pharmacogenomic databases to identify novel therapies. This reveals the copper ionophore elesclomol (ES) as highly effective against CRC-PMs. ES exhibits rapid cytotoxicity against CMS4 cells by targeting mitochondria. We find that a markedly reduced mitochondrial content in CMS4 cells explains their vulnerability to ES. ES demonstrates efficacy in preclinical models of PMs, including CRC-PMs and ovarian cancer organoids, mouse models, and a HIPEC rat model of PMs. The above proposes ES as a promising candidate for the local treatment of CRC-PMs, with broader implications for other PM-prone cancers.<br />Competing Interests: Declaration of interests L.V. is an employee and shareholder of Genentech-Roche. M.F.B. has received research funding from Celgene, Frame Therapeutics, and Lead Pharma and has acted as a consultant to Servier and Olympus.<br /> (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)
- Subjects :
- Animals
Humans
Mice
Cell Line, Tumor
Rats
Female
Hyperthermic Intraperitoneal Chemotherapy methods
Colorectal Neoplasms pathology
Colorectal Neoplasms drug therapy
Peritoneal Neoplasms secondary
Peritoneal Neoplasms drug therapy
Peritoneal Neoplasms therapy
Mitochondria metabolism
Mitochondria drug effects
Subjects
Details
- Language :
- English
- ISSN :
- 2666-3791
- Volume :
- 5
- Issue :
- 5
- Database :
- MEDLINE
- Journal :
- Cell reports. Medicine
- Publication Type :
- Academic Journal
- Accession number :
- 38670098
- Full Text :
- https://doi.org/10.1016/j.xcrm.2024.101523