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Metabolomic evaluation of Mitomycin C and rapamycin in a personalized treatment of pancreatic cancer

In a personalized treatment designed for a patient with pancreatic cancer resistant to other treatments, the success of Mitomycin C (MMC) has been highlighted. This was revealed in a murine xenograft tumor model encompassing pancreatic adenocarcinoma cells extracted from the patient. The patient was...

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Autores principales: Navarrete, Alicia, Armitage, Emily G, Musteanu, Monica, García, Antonia, Mastrangelo, Annalaura, Bujak, Renata, López-Casas, Pedro P, Hidalgo, Manuel, Barbas, Coral
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Blackwell Publishing Ltd 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4186447/
https://www.ncbi.nlm.nih.gov/pubmed/25505613
http://dx.doi.org/10.1002/prp2.67
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author Navarrete, Alicia
Armitage, Emily G
Musteanu, Monica
García, Antonia
Mastrangelo, Annalaura
Bujak, Renata
López-Casas, Pedro P
Hidalgo, Manuel
Barbas, Coral
author_facet Navarrete, Alicia
Armitage, Emily G
Musteanu, Monica
García, Antonia
Mastrangelo, Annalaura
Bujak, Renata
López-Casas, Pedro P
Hidalgo, Manuel
Barbas, Coral
author_sort Navarrete, Alicia
collection PubMed
description In a personalized treatment designed for a patient with pancreatic cancer resistant to other treatments, the success of Mitomycin C (MMC) has been highlighted. This was revealed in a murine xenograft tumor model encompassing pancreatic adenocarcinoma cells extracted from the patient. The patient was found to exhibit a biallelic inactivation of the PALB2 gene, involved in DNA repair in addition to another mutation in the TSC2 gene that induces susceptibility of the tumor to therapeutic targets of the PI3K-mTOR pathway. The aim of the study was to apply metabolomics to elucidate the modes of action of each therapy, suggesting why MMC was so successful in this patient and why it could be a more popular choice in future pancreatic cancer treatment. The effectiveness of MMC compared to rapamycin (RM), another relevant therapeutic agent has been evaluated through liquid- and gas-chromatography mass spectrometry-based metabolomic analyses of the xenograft tumors. The relative concentrations of many metabolites in the xenograft tumors were found to be increased by MMC relative to other treatments (RM and a combination of both), including a number that are involved in central carbon metabolism (CCM). Metabolic fingerprinting revealed statistically significantly altered pathways including, but not restricted to, the pentose phosphate pathway, glycolysis, TCA cycle, purine metabolism, fatty acid biosynthesis, in addition to many significant lipid and amino acid alterations. Given the genetic background of the patient, it was expected that the combined therapy would be most effective; however, the most effective was MMC alone. It is proposed that the effectiveness of MMC is owed to its direct effect on CCM, a vital region of tumor metabolism.
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spelling pubmed-41864472014-12-03 Metabolomic evaluation of Mitomycin C and rapamycin in a personalized treatment of pancreatic cancer Navarrete, Alicia Armitage, Emily G Musteanu, Monica García, Antonia Mastrangelo, Annalaura Bujak, Renata López-Casas, Pedro P Hidalgo, Manuel Barbas, Coral Pharmacol Res Perspect Original Articles In a personalized treatment designed for a patient with pancreatic cancer resistant to other treatments, the success of Mitomycin C (MMC) has been highlighted. This was revealed in a murine xenograft tumor model encompassing pancreatic adenocarcinoma cells extracted from the patient. The patient was found to exhibit a biallelic inactivation of the PALB2 gene, involved in DNA repair in addition to another mutation in the TSC2 gene that induces susceptibility of the tumor to therapeutic targets of the PI3K-mTOR pathway. The aim of the study was to apply metabolomics to elucidate the modes of action of each therapy, suggesting why MMC was so successful in this patient and why it could be a more popular choice in future pancreatic cancer treatment. The effectiveness of MMC compared to rapamycin (RM), another relevant therapeutic agent has been evaluated through liquid- and gas-chromatography mass spectrometry-based metabolomic analyses of the xenograft tumors. The relative concentrations of many metabolites in the xenograft tumors were found to be increased by MMC relative to other treatments (RM and a combination of both), including a number that are involved in central carbon metabolism (CCM). Metabolic fingerprinting revealed statistically significantly altered pathways including, but not restricted to, the pentose phosphate pathway, glycolysis, TCA cycle, purine metabolism, fatty acid biosynthesis, in addition to many significant lipid and amino acid alterations. Given the genetic background of the patient, it was expected that the combined therapy would be most effective; however, the most effective was MMC alone. It is proposed that the effectiveness of MMC is owed to its direct effect on CCM, a vital region of tumor metabolism. Blackwell Publishing Ltd 2014-12 2014-08-24 /pmc/articles/PMC4186447/ /pubmed/25505613 http://dx.doi.org/10.1002/prp2.67 Text en © 2014 The Authors. Pharmacology Research & Perspectives published by John Wiley & Sons Ltd, British Pharmacological Society and American Society for Pharmacology and Experimental Therapeutics. http://creativecommons.org/licenses/by-nc-nd/3.0/ This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.
spellingShingle Original Articles
Navarrete, Alicia
Armitage, Emily G
Musteanu, Monica
García, Antonia
Mastrangelo, Annalaura
Bujak, Renata
López-Casas, Pedro P
Hidalgo, Manuel
Barbas, Coral
Metabolomic evaluation of Mitomycin C and rapamycin in a personalized treatment of pancreatic cancer
title Metabolomic evaluation of Mitomycin C and rapamycin in a personalized treatment of pancreatic cancer
title_full Metabolomic evaluation of Mitomycin C and rapamycin in a personalized treatment of pancreatic cancer
title_fullStr Metabolomic evaluation of Mitomycin C and rapamycin in a personalized treatment of pancreatic cancer
title_full_unstemmed Metabolomic evaluation of Mitomycin C and rapamycin in a personalized treatment of pancreatic cancer
title_short Metabolomic evaluation of Mitomycin C and rapamycin in a personalized treatment of pancreatic cancer
title_sort metabolomic evaluation of mitomycin c and rapamycin in a personalized treatment of pancreatic cancer
topic Original Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4186447/
https://www.ncbi.nlm.nih.gov/pubmed/25505613
http://dx.doi.org/10.1002/prp2.67
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