title: Preclinical model of organotypic culture for pharmacodynamic profiling of human tumors.
abstract: Predicting drug response in cancer patients remains a major challenge in the clinic. We have perfected an ex vivo, reproducible, rapid and personalized culture method to investigate antitumoral pharmacological properties that preserves the original cancer microenvironment. Response to signal transduction inhibitors in cancer is determined not only by properties of the drug target but also by mutations in other signaling molecules and the tumor microenvironment. As a proof of concept, we, therefore, focused on the PI3K/Akt signaling pathway, because it plays a prominent role in cancer and its activity is affected by epithelial-stromal interactions. Our results show that this culture model preserves tissue 3D architecture, cell viability, pathway activity, and global gene-expression profiles up to 5 days ex vivo. In addition, we show pathway modulation in tumor cells resulting from pharmacologic intervention in ex vivo culture. This technology may have a significant impact on patient selection for clinical trials and in predicting response to small-molecule inhibitor therapy.
authors.affiliation: Department of Medicine, Surgery and Dentistry, Division of Pathology, University of Milan, AO San Paolo and Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, Milan 20142, Italy.
authors.forename: Valentina
authors.initials: V
authors.lastname: Vaira
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Fedele
authors.forename: Saumyadipta
authors.initials: S
authors.lastname: Pyne
authors.forename: Ester
authors.initials: E
authors.lastname: Fasoli
authors.forename: Giorgia
authors.initials: G
authors.lastname: Zadra
authors.forename: Dyane
authors.initials: D
authors.lastname: Bailey
authors.forename: Eric
authors.initials: E
authors.lastname: Snyder
authors.forename: Alice
authors.initials: A
authors.lastname: Faversani
authors.forename: Guido
authors.initials: G
authors.lastname: Coggi
authors.forename: Richard
authors.initials: R
authors.lastname: Flavin
authors.forename: Silvano
authors.initials: S
authors.lastname: Bosari
authors.forename: Massimo
authors.initials: M
authors.lastname: Loda
mesh_terms: D001706:Biopsy; D048430:Cell Shape; D002470:Cell Survival; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D009369:Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects*; D046509:Tissue Culture Techniques
chemical_list: D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors
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