title: The combination of sorafenib and everolimus shows antitumor activity in preclinical models of malignant pleural mesothelioma.
abstract: BACKGROUND
  Malignant Pleural Mesothelioma (MPM) is an aggressive tumor arising from mesothelial cells lining the pleural cavities characterized by resistance to standard therapies. Most of the molecular steps responsible for pleural transformation remain unclear; however, several growth factor signaling cascades are known to be altered during MPM onset and progression. Transducers of these pathways, such as PIK3CA-mTOR-AKT, MAPK, and ezrin/radixin/moesin (ERM) could therefore be exploited as possible targets for pharmacological intervention. This study aimed to identify 'druggable' pathways in MPM and to formulate a targeted approach based on the use of commercially available molecules, such as the multikinase inhibitor sorafenib and the mTOR inhibitor everolimus.
  
  
  METHODS
  We planned a triple approach based on: i) analysis of immunophenotypes and mutational profiles in a cohort of thoracoscopic MPM samples, ii) in vitro pharmacological assays, ii) in vivo therapeutic approaches on MPM xenografts. No mutations were found in 'hot spot' regions of the mTOR upstream genes (e.g. EGFR, KRAS and PIK3CA).
  
  
  RESULTS
  Phosphorylated mTOR and ERM were specifically overexpressed in the analyzed MPM samples. Sorafenib and everolimus combination was effective in mTOR and ERM blockade; exerted synergistic effects on the inhibition of MPM cell proliferation; triggered ROS production and consequent AMPK-p38 mediated-apoptosis. The antitumor activity was displayed when orally administered to MPM-bearing NOD/SCID mice.
  
  
  CONCLUSIONS
  ERM and mTOR pathways are activated in MPM and 'druggable' by a combination of sorafenib and everolimus. Combination therapy is a promising therapeutic strategy against MPM.
authors.affiliation: Division of Medical Oncology, IRCCS-Institute for Cancer Research and Treatment, Candiolo, (TO), 10060, Italy. ymera.pignochino@ircc.it.
authors.forename: Ymera
authors.initials: Y
authors.lastname: Pignochino
authors.affiliation: Division of Medical Oncology, IRCCS-Institute for Cancer Research and Treatment, Candiolo, (TO), 10060, Italy. carmine.dellaglio@ircc.it.
authors.forename: Carmine
authors.initials: C
authors.lastname: Dell'Aglio
authors.affiliation: Department of Molecular Medicine, - Section of Pneumology, Laboratory of Biochemistry & Genetics, University and Fondazione IRCCS Policlinico San Matteo, Pavia, 27100, Italy. s.inghilleri@smatteo.pv.it.
authors.forename: Simona
authors.initials: S
authors.lastname: Inghilleri
authors.affiliation: Department of Molecular Medicine, - Section of Pneumology, Laboratory of Biochemistry & Genetics, University and Fondazione IRCCS Policlinico San Matteo, Pavia, 27100, Italy. m.zorzetto@smatteo.pv.it.
authors.forename: Michele
authors.initials: M
authors.lastname: Zorzetto
authors.affiliation: Division of Medical Oncology, IRCCS-Institute for Cancer Research and Treatment, Candiolo, (TO), 10060, Italy. marco.soster@ircc.it.
authors.forename: Marco
authors.initials: M
authors.lastname: Basiricò
authors.affiliation: Division of Medical Oncology, IRCCS-Institute for Cancer Research and Treatment, Candiolo, (TO), 10060, Italy. federica.capozzi@ircc.it.
authors.forename: Federica
authors.initials: F
authors.lastname: Capozzi
authors.affiliation: Division of Medical Oncology, IRCCS-Institute for Cancer Research and Treatment, Candiolo, (TO), 10060, Italy. marta.canta@ircc.it.
authors.forename: Marta
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authors.lastname: Canta
authors.affiliation: Department of Molecular Medicine, - Section of Pneumology, Laboratory of Biochemistry & Genetics, University and Fondazione IRCCS Policlinico San Matteo, Pavia, 27100, Italy. d.piloni@smatteo.pv.it.
authors.forename: Davide
authors.initials: D
authors.lastname: Piloni
authors.affiliation: Department of Molecular Medicine, - Section of Pneumology, Laboratory of Biochemistry & Genetics, University and Fondazione IRCCS Policlinico San Matteo, Pavia, 27100, Italy. fracemmi@yahoo.com.
authors.forename: Francesca
authors.initials: F
authors.lastname: Cemmi
authors.affiliation: Division of Medical Oncology, IRCCS-Institute for Cancer Research and Treatment, Candiolo, (TO), 10060, Italy. dario.sangiolo@ircc.it.
authors.forename: Dario
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authors.lastname: Sangiolo
authors.affiliation: Division of Medical Oncology, IRCCS-Institute for Cancer Research and Treatment, Candiolo, (TO), 10060, Italy. loretta.gammaitoni@ircc.it.
authors.forename: Loretta
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authors.lastname: Gammaitoni
authors.affiliation: Laboratory of Tumor Microenvironment, IRCCS-Institute for Cancer Research and Treatment, Candiolo, (TO), 10060, Italy. marco.soster@ircc.it.
authors.forename: Marco
authors.initials: M
authors.lastname: Soster
authors.affiliation: Laboratory of Tumor Microenvironment, IRCCS-Institute for Cancer Research and Treatment, Candiolo, (TO), 10060, Italy. serena.marchio@ircc.it.
authors.forename: Serena
authors.initials: S
authors.lastname: Marchiò
authors.affiliation: Department of Molecular Medicine, - Section of Pneumology, Laboratory of Biochemistry & Genetics, University and Fondazione IRCCS Policlinico San Matteo, Pavia, 27100, Italy. ernesto.pozzi@unipv.it.
authors.forename: Ernesto
authors.initials: E
authors.lastname: Pozzi
authors.affiliation: Department of Molecular Medicine- Section of Pathology, University of Pavia and Fondazione IRCCS Policlinico San Matteo, Pavia, 27100, Italy. patrizia.morbini@unipv.it.
authors.forename: Patrizia
authors.initials: P
authors.lastname: Morbini
authors.affiliation: Department of Molecular Medicine, - Section of Pneumology, Laboratory of Biochemistry & Genetics, University and Fondazione IRCCS Policlinico San Matteo, Pavia, 27100, Italy. g.stella@smatteo.pv.it.
authors.forename: Maurizio
authors.initials: M
authors.lastname: Luisetti
authors.affiliation: Division of Medical Oncology, IRCCS-Institute for Cancer Research and Treatment, Candiolo, (TO), 10060, Italy. massimo.aglietta@ircc.it.
authors.forename: Massimo
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authors.lastname: Aglietta
authors.affiliation: Division of Medical Oncology, IRCCS-Institute for Cancer Research and Treatment, Candiolo, (TO), 10060, Italy. giovanni.grignani@ircc.it.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Grignani
authors.affiliation: Department of Molecular Medicine, - Section of Pneumology, Laboratory of Biochemistry & Genetics, University and Fondazione IRCCS Policlinico San Matteo, Pavia, 27100, Italy. g.stella@smatteo.pv.it.
authors.forename: Giulia M
authors.initials: GM
authors.lastname: Stella
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000494:pharmacology; D045744:Cell Line, Tumor; D003598:Cytoskeletal Proteins / Q000235:genetics / Q000378:metabolism*; D004357:Drug Synergism; D000068338:Everolimus / Q000008:administration & dosage* / Q000494:pharmacology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D008297:Male; D008654:Mesothelioma / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D051379:Mice; D009536:Niacinamide / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D010671:Phenylurea Compounds / Q000008:administration & dosage* / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D010997:Pleural Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D000077157:Sorafenib; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D016896:Treatment Outcome; D023041:Xenograft Model Antitumor Assays; D000099149:Ezrin
chemical_list: D003598:Cytoskeletal Proteins; D000068338:Everolimus; D009536:Niacinamide; D010671:Phenylurea Compounds; D000077157:Sorafenib; D058570:TOR Serine-Threonine Kinases; D000099149:Ezrin; C546842:MTOR protein, human