2. Academic Validation
  3. Exploiting a subtype-specific mitochondrial vulnerability for successful treatment of colorectal peritoneal metastases

Exploiting a subtype-specific mitochondrial vulnerability for successful treatment of colorectal peritoneal metastases

  • Cell Rep Med. 2024 Apr 22:101523. doi: 10.1016/j.xcrm.2024.101523.
Sanne Bootsma 1,  Mark P G Dings 1,  Job Kesselaar 1,  Roxan F C P A Helderman 2,  Kyah van Megesen 3,  Alexander Constantinides 3,  Leandro Ferreira Moreno 4,  Ellen Stelloo 5,  Enzo M Scutigliani 6,  Bella Bokan 2,  Arezo Torang 4,  Sander R van Hooff 4,  Danny A Zwijnenburg 7,  Valérie M Wouters 4,  Vincent C J van de Vlasakker 8,  Laskarina J K Galanos 8,  Lisanne E Nijman 4,  Adrian Logiantara 4,  Veronique L Veenstra 4,  Sophie Schlingemann 4,  Sterre van Piggelen 3,  Nicole van der Wel 9,  Przemek M Krawczyk 6,  Johannes J Platteeuw 10,  Jurriaan B Tuynman 11,  Ignace H de Hingh 12,  Jan P G Klomp 13,  Arthur Oubrie 13,  Petur Snaebjornsson 14,  Jan Paul Medema 4,  Arlene L Oei 2,  Onno Kranenburg 3,  Clara C Elbers 4,  Kristiaan J Lenos 4,  Louis Vermeulen 1,  Maarten F Bijlsma 15
Affiliations

Affiliations

  • 1 Amsterdam UMC Location University of Amsterdam, Center for Experimental and Molecular Medicine, Laboratory of Experimental Oncology and Radiobiology, Amsterdam, the Netherlands; Oncode Institute, Amsterdam, the Netherlands; Cancer Center Amsterdam, Cancer Biology, Amsterdam, the Netherlands; Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam, the Netherlands.
  • 2 Amsterdam UMC Location University of Amsterdam, Center for Experimental and Molecular Medicine, Laboratory of Experimental Oncology and Radiobiology, Amsterdam, the Netherlands; Cancer Center Amsterdam, Cancer Biology, Amsterdam, the Netherlands; Amsterdam UMC Location University of Amsterdam, Department of Radiation Oncology, Amsterdam, the Netherlands.
  • 3 Laboratory of Translational Oncology, UMC Utrecht Cancer Center, Utrecht, the Netherlands.
  • 4 Amsterdam UMC Location University of Amsterdam, Center for Experimental and Molecular Medicine, Laboratory of Experimental Oncology and Radiobiology, Amsterdam, the Netherlands; Oncode Institute, Amsterdam, the Netherlands; Cancer Center Amsterdam, Cancer Biology, Amsterdam, the Netherlands.
  • 5 Department of Genetics, Center for Molecular Medicine, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands.
  • 6 Cancer Center Amsterdam, Cancer Biology, Amsterdam, the Netherlands; Amsterdam UMC Location University of Amsterdam, Department of Medical Biology, Amsterdam, the Netherlands.
  • 7 Amsterdam UMC Location University of Amsterdam, Center for Experimental and Molecular Medicine, Laboratory of Experimental Oncology and Radiobiology, Amsterdam, the Netherlands; Cancer Center Amsterdam, Cancer Biology, Amsterdam, the Netherlands.
  • 8 Department of Surgery, Catharina Hospital, Eindhoven, the Netherlands.
  • 9 Amsterdam UMC Location University of Amsterdam, Electron Microscopy Center, Amsterdam, the Netherlands.
  • 10 Avivia Projects BV, Boxtel, the Netherlands.
  • 11 Amsterdam UMC Location Vrije Universiteit Amsterdam, Department of Surgery, Cancer Center Amsterdam, De Boelelaan 1117, Amsterdam, the Netherlands.
  • 12 Department of Surgery, Catharina Hospital, Eindhoven, the Netherlands; GROW - School for Oncology and Developmental Biology, Maastricht University, Maastricht, the Netherlands.
  • 13 Lead Pharma, Oss, the Netherlands.
  • 14 Department of Pathology, The Netherlands Cancer Institute, Amsterdam, the Netherlands.
  • 15 Amsterdam UMC Location University of Amsterdam, Center for Experimental and Molecular Medicine, Laboratory of Experimental Oncology and Radiobiology, Amsterdam, the Netherlands; Oncode Institute, Amsterdam, the Netherlands; Cancer Center Amsterdam, Cancer Biology, Amsterdam, the Netherlands. Electronic address: [email protected].
PMID: 38670098 DOI: 10.1016/j.xcrm.2024.101523
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.

Keywords

HIPEC; copper; elesclomol; mesenchymal cancer cell; mitochondria; molecular subtype; oxidative phosphorylation; peritoneal metastases.

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