title: Modeling Therapy Response and Spatial Tissue Distribution of Erlotinib in Pancreatic Cancer.
abstract: Pancreatic ductal adenocarcinoma (PDAC) is likely the most aggressive and therapy-resistant of all cancers. The aim of this study was to investigate the emerging technology of matrix-assisted laser desorption/ionization imaging mass spectrometry (MALDI IMS) as a powerful tool to study drug delivery and spatial tissue distribution in PDAC. We utilized an established genetically engineered mouse model of spontaneous PDAC to examine the distribution of the small-molecule inhibitor erlotinib in healthy pancreas and PDAC. MALDI IMS was utilized on sections of single-dose or long-term-treated mice to measure drug tissue distribution. Histologic and statistical analyses were performed to correlate morphology, drug distribution, and survival. We found that erlotinib levels were significantly lower in PDAC compared with healthy tissue (P = 0.0078). Survival of long-term-treated mice did not correlate with overall levels of erlotinib or with overall histologic tumor grade but did correlate both with the percentage of atypical glands in the cancer (P = 0.021, rs = 0.59) and the level of erlotinib in those atypical glands (P = 0.019, rs = 0.60). The results of this pilot study present MALDI IMS as a reliable technology to study drug delivery and spatial distribution of compounds in a preclinical setting and support drug imaging-based translational approaches. Mol Cancer Ther; 15(5); 1145-52. ©2016 AACR.
authors.affiliation: 2. Medizinische Klinik, Technische Universität München, Munich, Germany.
authors.forename: Barbara M
authors.initials: BM
authors.lastname: Grüner
authors.affiliation: Research Unit Analytical Pathology, Helmholtz Center Munich - German Research Center for Environmental Health, Neuherberg, Germany.
authors.forename: Isabel
authors.initials: I
authors.lastname: Winkelmann
authors.affiliation: Research Unit Analytical Pathology, Helmholtz Center Munich - German Research Center for Environmental Health, Neuherberg, Germany.
authors.forename: Annette
authors.initials: A
authors.lastname: Feuchtinger
authors.affiliation: Research Unit Analytical Pathology, Helmholtz Center Munich - German Research Center for Environmental Health, Neuherberg, Germany.
authors.forename: Na
authors.initials: N
authors.lastname: Sun
authors.affiliation: Center for Proteomics and Metabolomics, Leiden University Medical Center, Leiden, the Netherlands.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Balluff
authors.affiliation: 2. Medizinische Klinik, Technische Universität München, Munich, Germany.
authors.forename: Nicole
authors.initials: N
authors.lastname: Teichmann
authors.affiliation: 2. Medizinische Klinik, Technische Universität München, Munich, Germany.
authors.forename: Alexander
authors.initials: A
authors.lastname: Herner
authors.affiliation: 2. Medizinische Klinik, Technische Universität München, Munich, Germany.
authors.forename: Evdokia
authors.initials: E
authors.lastname: Kalideris
authors.affiliation: Institute of Pathology, Technische Universität München, Munich, Germany.
authors.forename: Katja
authors.initials: K
authors.lastname: Steiger
authors.affiliation: Institute of Radiology, Technische Universität München, Munich, Germany.
authors.forename: Rickmer
authors.initials: R
authors.lastname: Braren
authors.affiliation: Research Unit Analytical Pathology, Helmholtz Center Munich - German Research Center for Environmental Health, Neuherberg, Germany.
authors.forename: Michaela
authors.initials: M
authors.lastname: Aichler
authors.affiliation: Institute of Pathology, Heinrich-Heine-University, Düsseldorf, Germany.
authors.forename: Irene
authors.initials: I
authors.lastname: Esposito
authors.affiliation: 2. Medizinische Klinik, Technische Universität München, Munich, Germany. German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Roland M
authors.initials: RM
authors.lastname: Schmid
authors.affiliation: Research Unit Analytical Pathology, Helmholtz Center Munich - German Research Center for Environmental Health, Neuherberg, Germany. j.siveke@dkfz.de axel.walch@helmholtz-muenchen.de.
authors.forename: Axel
authors.initials: A
authors.lastname: Walch
authors.affiliation: 2. Medizinische Klinik, Technische Universität München, Munich, Germany. German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Heidelberg, Germany. Division of Solid Tumor Translational Oncology, German Cancer Consortium (DKTK) Partner Site Essen, West German Cancer Center, University Hospital Essen, Essen, Germany. j.siveke@dkfz.de axel.walch@helmholtz-muenchen.de.
authors.forename: Jens T
authors.initials: JT
authors.lastname: Siveke
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D016903:Drug Monitoring; D000069347:Erlotinib Hydrochloride / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D006801:Humans; D008279:Magnetic Resonance Imaging; D051379:Mice; D008822:Mice, Transgenic; D008954:Models, Biological; D060787:Neoplasm Grading; D010190:Pancreatic Neoplasms / Q000175:diagnosis / Q000188:drug therapy* / Q000401:mortality; D047428:Protein Kinase Inhibitors / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D016019:Survival Analysis; D013997:Time Factors; D014018:Tissue Distribution
chemical_list: D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D000069347:Erlotinib Hydrochloride