The combination of sorafenib and everolimus shows antitumor activity in preclinical models of malignant pleural mesothelioma

Ymera Pignochino, Carmine Dell'Aglio, Simona Inghilleri, Michele Zorzetto, Marco Basiricò, Federica Capozzi, Marta Canta, Davide Piloni, Francesca Cemmi, Dario Sangiolo, Loretta Gammaitoni, Marco Soster, Serena Marchiò, Ernesto Pozzi, Patrizia Morbini, Maurizio Luisetti, Massimo Aglietta, Giovanni Grignani, Giulia M. Stella

Research output: Contribution to journalArticle

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.

Original languageEnglish
Article number374
JournalBMC Cancer
Volume15
Issue number1
DOIs
Publication statusPublished - May 8 2015

Fingerprint

sorafenib
Everolimus
Malignant Mesothelioma
Pharmacology
erbB-1 Genes
Pleural Cavity
Inbred NOD Mouse
AMP-Activated Protein Kinases
SCID Mice
Therapeutics
Transducers
Heterografts
Intercellular Signaling Peptides and Proteins
Cell Proliferation
Apoptosis
Mutation
radixin
ezrin
moesin
Neoplasms

Keywords

  • Apoptosis
  • ezrin
  • Malignant pleural mesothelioma
  • mTOR
  • Preclinical models
  • Reactive oxygen species
  • Targeted therapy
  • Translational oncology

ASJC Scopus subject areas

  • Oncology
  • Cancer Research
  • Genetics

Cite this

The combination of sorafenib and everolimus shows antitumor activity in preclinical models of malignant pleural mesothelioma. / Pignochino, Ymera; Dell'Aglio, Carmine; Inghilleri, Simona; Zorzetto, Michele; Basiricò, Marco; Capozzi, Federica; Canta, Marta; Piloni, Davide; Cemmi, Francesca; Sangiolo, Dario; Gammaitoni, Loretta; Soster, Marco; Marchiò, Serena; Pozzi, Ernesto; Morbini, Patrizia; Luisetti, Maurizio; Aglietta, Massimo; Grignani, Giovanni; Stella, Giulia M.

In: BMC Cancer, Vol. 15, No. 1, 374, 08.05.2015.

Research output: Contribution to journalArticle

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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.",
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AU - Pignochino, Ymera

AU - Dell'Aglio, Carmine

AU - Inghilleri, Simona

AU - Zorzetto, Michele

AU - Basiricò, Marco

AU - Capozzi, Federica

AU - Canta, Marta

AU - Piloni, Davide

AU - Cemmi, Francesca

AU - Sangiolo, Dario

AU - Gammaitoni, Loretta

AU - Soster, Marco

AU - Marchiò, Serena

AU - Pozzi, Ernesto

AU - Morbini, Patrizia

AU - Luisetti, Maurizio

AU - Aglietta, Massimo

AU - Grignani, Giovanni

AU - Stella, Giulia M.

PY - 2015/5/8

Y1 - 2015/5/8

N2 - 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.

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KW - Targeted therapy

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