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Peritoneal Metastases from Colorectal Cancer belong to Consensus Molecular Subtype 4 and are sensitized 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 tumor regions and 59 paired PM from 12 patients. All samples were analyzed 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 tumors 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 sensitized PMDOs to a 1-hour 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

ORGANISM(S): Homo sapiens

PROVIDER: GSE190609 | GEO | 2022/06/15

REPOSITORIES: GEO

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Project description:Claret2009 - Predicting phase III overall survival in colorectal cancer This model is described in the article: Model-based prediction of phase III overall survival in colorectal cancer on the basis of phase II tumor dynamics. Claret L, Girard P, Hoff PM, Van Cutsem E, Zuideveld KP, Jorga K, Fagerberg J, Bruno R. J. Clin. Oncol. 2009 Sep; 27(25): 4103-4108 Abstract: PURPOSE: We developed a drug-disease simulation model to predict antitumor response and overall survival in phase III studies from longitudinal tumor size data in phase II trials. METHODS: We developed a longitudinal exposure-response tumor-growth inhibition (TGI) model of drug effect (and resistance) using phase II data of capecitabine (n = 34) and historical phase III data of fluorouracil (FU; n = 252) in colorectal cancer (CRC); and we developed a parametric survival model that related change in tumor size and patient characteristics to survival time using historical phase III data (n = 245). The models were validated in simulation of antitumor response and survival in an independent phase III study (n = 1,000 replicates) of capecitabine versus FU in CRC. RESULTS: The TGI model provided a good fit of longitudinal tumor size data. A lognormal distribution best described the survival time, and baseline tumor size and change in tumor size from baseline at week 7 were predictors (P < .00001). Predicted change of tumor size and survival time distributions in the phase III study for both capecitabine and FU were consistent with observed values, for example, 431 days (90% prediction interval, 362 to 514 days) versus 401 days observed for survival in the capecitabine arm. A modest survival improvement of 39 days (90% prediction interval, -21 to 110 days) versus 35 days observed was predicted for capecitabine. CONCLUSION: The modeling framework successfully predicted survival in a phase III trial on the basis of capecitabine phase II data in CRC. It is a useful tool to support end-of-phase II decisions and design of phase III studies. This model is hosted on BioModels Database and identified by: MODEL1708310001. To cite BioModels Database, please use: BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models. To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication for more information.

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Peritoneal Metastases from Colorectal Cancer belong to Consensus Molecular Subtype 4 and are sensitized to oxaliplatin by inhibiting reducing capacity

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