Dataset Information

Peritoneal metastases from colorectal cancer belong to Consensus Molecular Subtype 4 and are sensitised to oxaliplatin by inhibiting reducing capacity.

ABSTRACT:

Background

Peritoneal metastases (PM) in colorectal cancer (CRC) are associated with therapy resistance and poor survival. Oxaliplatin monotherapy is widely applied in the intraperitoneal treatment of PM, but fails to yield clinical benefit. We aimed to identify the mechanism(s) underlying PM resistance to oxaliplatin and to develop strategies overcoming such resistance.

Experimental design

We generated a biobank consisting of 35 primary tumour regions and 59 paired PM from 12 patients. All samples were analysed by RNA sequencing. We also generated a series of PM-derived organoid (PMDO) cultures and used these to design and test strategies to overcome resistance to oxaliplatin.

Results

PM displayed various hallmarks of aggressive CRC biology. The vast majority of PM and paired primary tumours belonged to the Consensus Molecular Subtype 4 (CMS4). PMDO cultures were resistant to oxaliplatin and expressed high levels of glutamate-cysteine ligase (GCLC) causing detoxification of oxaliplatin through glutathione synthesis. Genetic or pharmacological targeting of GCLC sensitised PMDOs to a 1-h exposure to oxaliplatin, through increased platinum-DNA adduct formation.

Conclusions

These results link oxaliplatin resistance of colorectal PM to their CMS4 status and high reducing capacity. Inhibiting the reducing capacity of PM may be an effective strategy to overcome PM resistance to oxaliplatin.

SUBMITTER: Laoukili J

PROVIDER: S-EPMC9174226 | biostudies-literature | 2022 Jun

REPOSITORIES: biostudies-literature

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Publications

Peritoneal metastases from colorectal cancer belong to Consensus Molecular Subtype 4 and are sensitised to oxaliplatin by inhibiting reducing capacity.

Laoukili Jamila J Constantinides Alexander A Wassenaar Emma C E ECE Elias Sjoerd G SG Raats Danielle A E DAE van Schelven Susanne J SJ van Wettum Jonathan J Volckmann Richard R Koster Jan J Huitema Alwin D R ADR Nienhuijs Simon W SW de Hingh Ignace H J T IHJT Wiezer René J RJ van Grevenstein Helma M U HMU Rinkes Inne H M Borel IHMB Boerma Djamila D Kranenburg Onno O

British journal of cancer 20220222 12

<h4>Background</h4>Peritoneal metastases (PM) in colorectal cancer (CRC) are associated with therapy resistance and poor survival. Oxaliplatin monotherapy is widely applied in the intraperitoneal treatment of PM, but fails to yield clinical benefit. We aimed to identify the mechanism(s) underlying PM resistance to oxaliplatin and to develop strategies overcoming such resistance.<h4>Experimental design</h4>We generated a biobank consisting of 35 primary tumour regions and 59 paired PM from 12 pat ...[more]

PMID: 35194192

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Project description:Pressurized intraperitoneal aerosol chemotherapy with oxaliplatin (PIPAC-OX) is increasingly used as a palliative treatment option for patients with colorectal peritoneal metastases (CPM). The present study aimed to systematically review all clinical studies reporting safety and efficacy outcomes of PIPAC-OX in patients with CPM. PubMed, EMBASE, The Cochrane Library, and CINAHL were systematically searched to identify all clinical studies that included at least one patient with CPM treated with PIPAC-OX and reported one of the following outcomes: adverse events, tumor response, quality of life, secondary cytoreductive surgery, progression-free survival, overall survival, and environmental safety of PIPAC-OX. Results were narratively described. Of 28 included studies, only 14 non-comparative studies separately reported at least one outcome of PIPAC-OX for CPM, of which only two studies specifically focused on this group. These 14 studies reported adverse events (5 studies), tumor response (5 studies), secondary cytoreductive surgery (4 studies), progression-free survival (1 study), overall survival (5 studies), and environmental safety (2 studies). Except for 5 studies (describing 26 patients), none of the included studies stratified their results for PIPAC-OX monotherapy and PIPAC-OX with concomitant systemic therapy, and none of the studies reporting survival outcomes stratified results for line of palliative treatment, complicating interpretation. No PIPAC-OX related deaths were reported. No occupational platinum was detected during PIPAC-OX. The available evidence regarding PIPAC-OX for CPM is limited and difficult to interpret. Despite these limitations, PIPAC-OX appears safe in patients with CPM and safe for operating personnel. To increase insight in the role of PIPAC-OX in this setting, investigators of ongoing and future studies are encouraged to report separate outcomes of PIPAC-OX for CPM, to stratify their results for PIPAC-OX monotherapy and PIPAC-OX with concomitant systemic therapy, and to stratify survival results for line of palliative treatment.

Dataset Information

Peritoneal metastases from colorectal cancer belong to Consensus Molecular Subtype 4 and are sensitised to oxaliplatin by inhibiting reducing capacity.

Background

Experimental design

Results

Conclusions

Publications

Peritoneal metastases from colorectal cancer belong to Consensus Molecular Subtype 4 and are sensitised to oxaliplatin by inhibiting reducing capacity.

Similar Datasets

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