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
Division of Medical Oncology, IRCCS-Institute for Cancer Research and Treatment, Candiolo, (TO), 10060, Italy.
Department of Molecular Medicine, - Section of Pneumology, Laboratory of Biochemistry & Genetics, University and Fondazione IRCCS Policlinico San Matteo, Pavia, 27100, Italy.
BMC Cancer. 2015 May 8;15:374. doi: 10.1186/s12885-015-1363-1.
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.
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).
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.
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.
恶性胸膜间皮瘤（MPM）是一种起源于胸膜腔间皮细胞的侵袭性肿瘤，其特点是对标准治疗具有抗性。导致胸膜转化的大多数分子步骤仍不清楚；然而，已知在MPM的发生和发展过程中，几个生长因子信号级联会发生改变。因此，这些信号通路的转导分子，如PIK3CA-mTOR-AKT、MAPK和埃兹蛋白/根蛋白/膜突蛋白（ERM），可作为药物干预的潜在靶点。本研究旨在确定MPM中“可成药”的信号通路，并基于使用市售分子，如多激酶抑制剂索拉非尼和mTOR抑制剂依维莫司，制定一种靶向治疗方法。
我们计划采用三重方法，包括：i）分析一组胸腔镜MPM样本的免疫表型和突变谱，ii）体外药理学试验，iii）对MPM异种移植瘤进行体内治疗。在mTOR上游基因（如EGFR、KRAS和PIK3CA）的“热点”区域未发现突变。
磷酸化的mTOR和ERM在分析的MPM样本中特异性过表达。索拉非尼和依维莫司联合使用在阻断mTOR和ERM方面有效；对抑制MPM细胞增殖发挥协同作用；触发活性氧（ROS）产生并随之引发AMPK-p38介导的细胞凋亡。口服给药于荷MPM的NOD/SCID小鼠时显示出抗肿瘤活性。
ERM和mTOR信号通路在MPM中被激活，并且可被索拉非尼和依维莫司联合“靶向治疗”。联合治疗是一种有前景的MPM治疗策略。
