title: Metabolomic evaluation of Mitomycin C and rapamycin in a personalized treatment of pancreatic cancer.
abstract: 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.
authors.affiliation: CEMBIO (Center for Metabolomics and Bioanalysis), Facultad de Farmacia, Universidad CEU San Pablo Campus Montepríncipe, Boadilla del Monte, 28668, Madrid, Spain.
authors.forename: Alicia
authors.initials: A
authors.lastname: Navarrete
authors.affiliation: CEMBIO (Center for Metabolomics and Bioanalysis), Facultad de Farmacia, Universidad CEU San Pablo Campus Montepríncipe, Boadilla del Monte, 28668, Madrid, Spain.
authors.forename: Emily G
authors.initials: EG
authors.lastname: Armitage
authors.affiliation: CNIO (Spanish National Cancer Research Centre) E-28029, Madrid, Madrid, Spain.
authors.forename: Monica
authors.initials: M
authors.lastname: Musteanu
authors.affiliation: CEMBIO (Center for Metabolomics and Bioanalysis), Facultad de Farmacia, Universidad CEU San Pablo Campus Montepríncipe, Boadilla del Monte, 28668, Madrid, Spain.
authors.forename: Antonia
authors.initials: A
authors.lastname: García
authors.affiliation: CEMBIO (Center for Metabolomics and Bioanalysis), Facultad de Farmacia, Universidad CEU San Pablo Campus Montepríncipe, Boadilla del Monte, 28668, Madrid, Spain.
authors.forename: Annalaura
authors.initials: A
authors.lastname: Mastrangelo
authors.affiliation: CEMBIO (Center for Metabolomics and Bioanalysis), Facultad de Farmacia, Universidad CEU San Pablo Campus Montepríncipe, Boadilla del Monte, 28668, Madrid, Spain ; Department of Biopharmacy and Pharmacodynamics, Medical University of Gdansk Al. Hallera 107, Gdansk, 80-416, Poland.
authors.forename: Renata
authors.initials: R
authors.lastname: Bujak
authors.affiliation: CNIO (Spanish National Cancer Research Centre) E-28029, Madrid, Madrid, Spain.
authors.forename: Pedro P
authors.initials: PP
authors.lastname: López-Casas
authors.affiliation: CNIO (Spanish National Cancer Research Centre) E-28029, Madrid, Madrid, Spain.
authors.forename: Manuel
authors.initials: M
authors.lastname: Hidalgo
authors.affiliation: CEMBIO (Center for Metabolomics and Bioanalysis), Facultad de Farmacia, Universidad CEU San Pablo Campus Montepríncipe, Boadilla del Monte, 28668, Madrid, Spain.
authors.forename: Coral
authors.initials: C
authors.lastname: Barbas
keywords: Central carbon metabolism; PALB2; mTOR; metabolomics; pancreatic cancer