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

Sanne Bootsma; Mark P.G. Dings; Job Kesselaar; Roxan F.C.P.A. 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 J.K. 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; Petur Snaebjornsson; Jan Paul Medema; Arlene L. Oei; Onno Kranenburg; Clara C. Elbers; Kristiaan J. Lenos; Louis Vermeulen; Maarten F. Bijlsma

doi:10.1016/j.xcrm.2024.101523

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

Sanne Bootsma, Mark P.G. Dings, Job Kesselaar, Roxan F.C.P.A. 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 J.K. Galanos, Lisanne E. Nijman, Adrian Logiantara, Veronique L. Veenstra, Sophie SchlingemannSterre 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, Petur Snaebjornsson, Jan Paul Medema, Arlene L. Oei, Onno Kranenburg, Clara C. Elbers, Kristiaan J. Lenos, Louis Vermeulen, Maarten F. Bijlsma^*

^*Corresponding author for this work

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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.

Original language	English
Article number	101523
Journal	Cell Reports Medicine
Volume	5
Issue number	5
DOIs	https://doi.org/10.1016/j.xcrm.2024.101523
Publication status	Published - 21 May 2024

Keywords

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

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Bootsma, S., Dings, M. P. G., Kesselaar, J., Helderman, R. F. C. P. A., van Megesen, K., Constantinides, A., Moreno, L. F., Stelloo, E., Scutigliani, E. M., Bokan, B., Torang, A., van Hooff, S. R., Zwijnenburg, D. A., Wouters, V. M., van de Vlasakker, V. C. J., Galanos, L. J. K., Nijman, L. E., Logiantara, A., Veenstra, V. L., ... Bijlsma, M. F. (2024). Exploiting a subtype-specific mitochondrial vulnerability for successful treatment of colorectal peritoneal metastases. Cell Reports Medicine, 5(5), Article 101523. https://doi.org/10.1016/j.xcrm.2024.101523

@article{70aa245fad4c47d2a5ebcfd139cecb29,

title = "Exploiting a subtype-specific mitochondrial vulnerability for successful treatment of colorectal peritoneal metastases",

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 = "copper, elesclomol, HIPEC, mesenchymal cancer cell, mitochondria, molecular subtype, oxidative phosphorylation, peritoneal metastases",

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

note = "Publisher Copyright: {\textcopyright} 2024 The Authors",

year = "2024",

month = may,

day = "21",

doi = "10.1016/j.xcrm.2024.101523",

language = "English",

volume = "5",

number = "5",

}

Bootsma, S, Dings, MPG, Kesselaar, J, Helderman, RFCPA, van Megesen, K, Constantinides, A, Moreno, LF, Stelloo, E, Scutigliani, EM, Bokan, B, Torang, A, van Hooff, SR, Zwijnenburg, DA, Wouters, VM, van de Vlasakker, VCJ, Galanos, LJK, Nijman, LE, Logiantara, A, Veenstra, VL, Schlingemann, S, van Piggelen, S, van der Wel, N, Krawczyk, PM, Platteeuw, JJ, Tuynman, JB, de Hingh, IH, Klomp, JPG, Oubrie, A, Snaebjornsson, P, Medema, JP, Oei, AL, Kranenburg, O, Elbers, CC, Lenos, KJ, Vermeulen, L & Bijlsma, MF 2024, 'Exploiting a subtype-specific mitochondrial vulnerability for successful treatment of colorectal peritoneal metastases', Cell Reports Medicine, vol. 5, no. 5, 101523. https://doi.org/10.1016/j.xcrm.2024.101523

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 - copper

KW - elesclomol

KW - HIPEC

KW - mesenchymal cancer cell

KW - mitochondria

KW - molecular subtype

KW - oxidative phosphorylation

KW - peritoneal metastases

UR - http://www.scopus.com/inward/record.url?scp=85192489549&partnerID=8YFLogxK

U2 - 10.1016/j.xcrm.2024.101523

DO - 10.1016/j.xcrm.2024.101523

M3 - Article

C2 - 38670098

AN - SCOPUS:85192489549

SN - 2666-3791

VL - 5

JO - Cell Reports Medicine

JF - Cell Reports Medicine

IS - 5

M1 - 101523

ER -

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

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