TY - JOUR
T1 - Exploiting a subtype-specific mitochondrial vulnerability for successful treatment of colorectal peritoneal metastases
AU - Bootsma, Sanne
AU - Dings, Mark P G
AU - Kesselaar, Job
AU - Helderman, Roxan F C P A
AU - van Megesen, Kyah
AU - Constantinides, Alexander
AU - Moreno, Leandro Ferreira
AU - Stelloo, Ellen
AU - Scutigliani, Enzo M
AU - Bokan, Bella
AU - Torang, Arezo
AU - van Hooff, Sander R
AU - Zwijnenburg, Danny A
AU - Wouters, Valérie M
AU - van de Vlasakker, Vincent C J
AU - Galanos, Laskarina J K
AU - Nijman, Lisanne E
AU - Logiantara, Adrian
AU - Veenstra, Veronique L
AU - Schlingemann, Sophie
AU - van Piggelen, Sterre
AU - van der Wel, Nicole
AU - Krawczyk, Przemek M
AU - Platteeuw, Johannes J
AU - Tuynman, Jurriaan B
AU - de Hingh, Ignace H
AU - Klomp, Jan P G
AU - Oubrie, Arthur
AU - Snaebjornsson, Petur
AU - Medema, Jan Paul
AU - Oei, Arlene L
AU - Kranenburg, Onno
AU - Elbers, Clara C
AU - Lenos, Kristiaan J
AU - Vermeulen, Louis
AU - Bijlsma, Maarten F
PY - 2024/5/21
Y1 - 2024/5/21
N2 - 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.
AB - 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.
KW - HIPEC
KW - copper
KW - elesclomol
KW - mesenchymal cancer cell
KW - mitochondria
KW - molecular subtype
KW - oxidative phosphorylation
KW - peritoneal metastases
U2 - 10.1016/j.xcrm.2024.101523
DO - 10.1016/j.xcrm.2024.101523
M3 - Article
SN - 2666-3791
VL - 5
JO - Cell Reports Medicine
JF - Cell Reports Medicine
IS - 5
M1 - 101523
ER -