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

BMC Cancer

Research Article

Davide Piloni¹  Giulia M Stella¹  Maurizio Luisetti¹  Francesca Cemmi¹  Simona Inghilleri¹  Ernesto Pozzi¹  Michele Zorzetto¹  Patrizia Morbini²  Federica Capozzi³  Giovanni Grignani³  Marco Basiricò³  Marta Canta³  Loretta Gammaitoni³  Massimo Aglietta³  Ymera Pignochino³  Carmine Dell’Aglio³  Dario Sangiolo³  Marco Soster⁴  Serena Marchiò⁴ 

[1] Department of Molecular Medicine, − Section of Pneumology, Laboratory of Biochemistry & Genetics, University and Fondazione IRCCS Policlinico San Matteo, 27100, Pavia, Italy;Department of Molecular Medicine- Section of Pathology, University of Pavia and Fondazione IRCCS Policlinico San Matteo, 27100, Pavia, Italy;Division of Medical Oncology, IRCCS-Institute for Cancer Research and Treatment, Candiolo, 10060, (TO), Italy;Laboratory of Tumor Microenvironment, IRCCS-Institute for Cancer Research and Treatment, Candiolo, 10060, (TO), Italy;

关键词: mTOR;    ezrin;    Malignant pleural mesothelioma;    Targeted therapy;    Preclinical models;    Apoptosis;    Reactive oxygen species;    Translational oncology;   

DOI  :  10.1186/s12885-015-1363-1

 received in 2014-04-25, accepted in 2015-04-24,  发布年份 2015

来源: Springer

【 摘 要 】

BackgroundMalignant 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.MethodsWe 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).ResultsPhosphorylated 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.ConclusionsERM 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.

【 授权许可】

Unknown   
© Pignochino et al.; licensee BioMed Central. 2015. This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.