Preclinical model of organotypic culture for pharmacodynamic profiling of human tumors.
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.
Vaira
Valentina
V
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.
Fedele
Giuseppe
G
Pyne
Saumyadipta
S
Fasoli
Ester
E
Zadra
Giorgia
G
Bailey
Dyane
D
Snyder
Eric
E
Faversani
Alice
A
Coggi
Guido
G
Flavin
Richard
R
Bosari
Silvano
S
Loda
Massimo
M
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
D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors
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