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

Our plain-English summary of The combination of sorafenib and everolimus shows antitumor activity in preclinical models of malignant pleural mesothelioma, by Y. Pignochino, C. Dell'Aglio, S. Inghilleri, et al (BMC Cancer, 2015).

The study

• Authors: Y. Pignochino, C. Dell'Aglio, S. Inghilleri, M. Zorzetto, M. Basiricò, F. Capozzi, M. Canta, D. Piloni, F. Cemmi, D. Sangiolo, L. Gammaitoni, M. Soster, S. Marchiò, E. Pozzi, P. Morbini, M. Luisetti, M. Aglietta, G. Grignani, G.M. Stella
• Journal: BMC Cancer
• Published: 2015;15:374
• Cited by: 27 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

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.

In plain English

This laboratory study from Italy tested whether two existing cancer drugs, sorafenib and everolimus, act against malignant pleural mesothelioma. It did not study asbestos exposure itself, though all 30 patients whose tumor samples were analyzed reported occupational or environmental asbestos exposure. The researchers examined 30 thoracoscopy samples (10 epithelioid, 10 biphasic, 10 sarcomatous). They then tested the drugs on mesothelioma cell lines and on human mesothelioma tumors grown under the skin of mice. Activated mTOR was found in 83% of samples and activated ERM proteins in 93%. No mutations were found in the tested regions of the EGFR, KRAS and PIK3CA genes. In the cell lines, the two drugs together had a synergistic effect on cell viability. In one cell line, 85.42% of cells treated with the combination were apoptotic (undergoing programmed cell death), compared with 25.99% of untreated cells. In mice, the combination reduced tumor growth more than either drug alone or no drug. The authors concluded that the results encourage planning phase II trials in patients. They noted that their selected sample set does not reflect the biology of mesothelioma.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Preclinical laboratory study with three parts: analysis of human tumor samples, experiments on cultured mesothelioma cell lines, and a treatment experiment in mice carrying human mesothelioma tumors (xenografts)
• Who was studied: 30 malignant pleural mesothelioma samples (10 of each histological subtype) from patients aged 18 or older at Fondazione IRCCS Policlinico San Matteo, Pavia, Italy. Also nine mesothelioma cell lines, and 24 female NOD/SCID mice injected with MSTO-211H cells.
• Exposure: The exposure studied was treatment, not asbestos: sorafenib (a multikinase inhibitor) and everolimus (an mTOR inhibitor), alone or combined. In mice the doses were sorafenib 5 mg/kg/day and everolimus 1 mg/kg/day by mouth for 4 weeks. No asbestos fiber type is named.
• Main results:
  • All 30 patients whose samples were analyzed reported occupational or environmental exposure to asbestos.
  • Phosphorylated (activated) mTOR was found in 83% of the 30 tumor samples, in both sarcomatous and epithelial subtypes.
  • Phosphorylated ERM proteins were present at moderate-high levels in 93% of the tumor samples.
  • No somatic mutations were found in the tested hot-spot regions of the EGFR, KRAS and PIK3CA genes in the tumor samples.
  • In cultured cell lines, everolimus alone had a weak effect, lowering cell vitality by 20% to 30% at the highest tested dose.
  • In cultured cell lines, the combination reduced cell viability more than either drug alone and showed synergism (combination index below 1).
  • In MES-MM98 cells, 67.31% of cells treated with sorafenib alone were apoptotic, compared with 25.99% of vehicle-treated control cells.
  • In MES-MM98 cells, 85.42% of cells treated with the combination were apoptotic.
  • In mice with mesothelioma xenografts, the combination reduced tumor growth more than either drug alone or vehicle (p less than 0.05).
  • The authors reported that treatment did not impair the general health of the treated mice.
• The authors' conclusion: The authors concluded that everolimus and sorafenib have antitumor activity in preclinical models of human malignant pleural mesothelioma, and that this encourages planning phase II trials of the combination in patients.
• Limitations the authors state:
  • The tumor sample set was chosen as 10 cases of each histological subtype and so, the authors state, does not reflect the biology of the disease.
  • The mouse tumors were grown under the skin. The authors state that the treatment still needs to be tested on tumors grown in their natural location (orthotopically).

Topics

The National Library of Medicine indexes this study under subjects our site covers: Mesothelioma.

Medical terms in this study, explained in our Lexicon: Sorafenib (Nexavar), Pleural Mesothelioma, Mesothelial Cells, EGFR, Synergistic Effect, Apoptosis.

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• Phase 2 study of sorafenib in malignant mesothelioma previously treated with platinum-containing chemotherapy — S. Papa, S. Popat, et al. (2013)
• Synergistic antitumor activity of recombinant human Apo2L/tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) in combination with carboplatin and pemetrexed in malignant pleural mesothelioma — G. Pasello, L. Urso, et al. (2014)
• Antitumor activity of type III interferon alone or in combination with type I interferon against human non-small cell lung cancer — H. Fujie, T. Tanaka, et al. (2011)
• A phase II study of sorafenib in malignant mesothelioma: results of Cancer and Leukemia Group B 30307 — S. Dubey, P.A. Jänne, et al. (2010)
• Preclinical demonstration of synergistic Active Nutrients/Drug (AND) combination as a potential treatment for malignant pleural mesothelioma — V. Volta, E. Ranzato, et al. (2013)

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