作者
Sanne Bootsma,Mark P.G. Dings,Job Kesselaar,Roxan F.C.P. Helderman,Kyah van Megesen,Alexander Constantinides,Leandro Ferreira Moreno,Ellen Stelloo,Enzo M. Scutigliani,Bella Bokan,Arezo Torang,Sander R. van Hooff,Danny A. Zwijnenburg,Valérie M. Wouters,Vincent C. J. van de Vlasakker,Laskarina Galanos,Lisanne E. Nijman,Adrian Logiantara,Veronique L. Veenstra,Sophie Schlingemann,Sterre van Piggelen,Nicole van der Wel,Przemek M. Krawczyk,Johannes J. Platteeuw,Jurriaan B. Tuynman,Ignace H. de Hingh,Jan P.G. Klomp,Arthur Oubrie,Pétur Snæbjörnsson,Jan Paul Medema,Arlene L. Oei,Onno Kranenburg,Clara C. Elbers,Kristiaan Lenos,Louis Vermeulen,Maarten F. Bijlsma
摘要
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.