Temsirolimus inhibits malignant pleural mesothelioma growth in vitro and in vivo: synergism with chemotherapy

Our plain-English summary of Temsirolimus inhibits malignant pleural mesothelioma growth in vitro and in vivo: synergism with chemotherapy, by M.A. Hoda, A. Mohamed, B. Ghanim, et al (Journal of Thoracic Oncology, 2011).

The study

• Authors: M.A. Hoda, A. Mohamed, B. Ghanim, M. Filipits, B. Hegedus, M. Tamura, J. Berta, B. Kubista, B. Dome, M. Grusch, U. Setinek, M. Micksche, W. Klepetko, W. Berger
• Journal: Journal of Thoracic Oncology
• Published: 2011;6(5):852-63
• Cited by: 35 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Introduction: Human malignant pleural mesothelioma (MPM) is an asbestos-related malignancy characterized by frequent resistance to chemotherapy and radiotherapy. Here, we investigated the feasibility of mammalian target of rapamycin (mTOR) inhibition by temsirolimus as an antimesothelioma strategy.

Methods: Phosphorylation of mTOR (p-mTOR) was assessed by immunohistochemistry in MPM surgical specimens (n = 70). Activation of mTOR and impact of mTOR inhibition by temsirolimus was determined in MPM cell lines in vitro (n = 6) and in vivo as xenografts in severe combined immunodeficiency mice (n = 2) either as single agent or in combination with cisplatin.

Results: Strong immunoreactivity for p-mTOR was predominantly detected in epitheloid and biphasic but not sarcomatoid MPM specimens while adjacent normal tissues remained widely unstained. Accordingly, all mesothelioma cell lines harbored activated mTOR, which was further confirmed by hyperphosphorylation of the downstream targets pS6K, S6, and 4EBP1. Temsirolimus potently blocked mTOR-mediated signals and exerted a cytostatic effect on mesothelioma cell lines in vitro cultured both as adherent monolayers and as nonadherent spheroids. Mesothelioma cells with intrinsic or acquired cisplatin resistance exhibited hypersensitivity against temsirolimus. Accordingly, cisplatin and temsirolimus exerted synergistic inhibition of the mTOR downstream signals and enhanced growth inhibition and/or apoptosis induction in mesothelioma cell lines. Finally, temsirolimus was highly active against MPM xenograft models in severe combined immunodeficiency mice both as a single agent and in combination with cisplatin.

Conclusion: The mTOR inhibitor temsirolimus is active against mesothelioma in vitro and in vivo and synergizes with chemotherapy. These data suggest mTOR inhibition as a promising novel therapeutic strategy against MPM.

In plain English

This laboratory study tested whether the drug temsirolimus, which blocks a growth-signalling protein called mTOR, acts against malignant pleural mesothelioma. It did not study asbestos exposure. The authors stained tumor tissue from 70 patients operated on in Vienna between 1993 and 2010. They tested the drug, alone and with the chemotherapy drug cisplatin, on six mesothelioma cell lines and on tumors grown in the abdomen of immune-deficient mice. Activated mTOR was found mostly in epitheloid tumors (mean score 55) rather than sarcomatoid ones (mean score 2). It was not significantly linked to patient survival. Cell lines resistant to cisplatin were especially sensitive to temsirolimus, and in cells the two drugs together mostly acted synergistically. In mice, median tumor weight at day 38 was 48 mg with temsirolimus versus 225 mg in controls. In one mouse model, mean survival was 46 days untreated, 60 with temsirolimus, 71 with cisplatin and 83 with both. The authors concluded that temsirolimus is active against mesothelioma in these models and called for further investigation.

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: staining of stored human tumor tissue, cell-culture experiments, and animal experiments with human mesothelioma grown in mice (xenografts)
• Who was studied: Tumor tissue from 70 patients with histologically confirmed MPM who had surgery between January 1993 and January 2010 at the Medical University of Vienna. The tissue comprised 43 epitheloid, 19 biphasic, 4 sarcomatoid and 4 pseudomesotheliomatous adenocarcinomas. The study also used six MPM cell lines (SPC111, SPC212, NCI-H28, NCI-H2052, P31 and its cisplatin-resistant subline P31res1.2) and female SCID mice (80 in total) injected in the abdomen with SPC111 or P31 cells.
• Exposure: No asbestos exposure was studied. The treatments tested were temsirolimus (in mice, 10 mg/kg daily in two cycles) and cisplatin (in mice, 1 mg/kg once a week for 2 weeks), alone or combined, all given into the abdomen. Cells were also treated with a range of drug concentrations.
• Main results:
  • In patient tumor tissue, activated (phosphorylated) mTOR was stronger in epitheloid than in sarcomatoid tumors (mean staining score 55 versus 2).
  • Among epitheloid tumors, the mean staining score was 66 in early-stage versus 46 in late-stage disease.
  • In the 70 patients, overall survival did not correlate significantly with the intensity of activated mTOR staining.
  • All investigated mesothelioma cell lines showed strong activation of mTOR.
  • The cisplatin-resistant subline P31res1.2 showed significant hypersensitivity to temsirolimus.
  • In all cell lines tested, temsirolimus combined with cisplatin produced predominantly synergistic effects. Antagonistic effects were seen only occasionally, at high temsirolimus concentrations.
  • In the cisplatin-resistant P31res1.2 cells, the combination of both drugs was reported to induce 75% apoptotic (dying) nuclei.
  • In mice at 38 days after tumor transplantation, median tumor weight was 225 mg in controls versus 48 mg with temsirolimus.
  • Mean overall survival of mice was 52 days for controls versus 62 days with temsirolimus in the SPC111 model, and 45 versus 57 days in the P31 model.
  • At tumor progression, median tumor necrotic area was 1% in controls versus 51% with temsirolimus.
  • In the SPC111 mouse model, mean overall survival was 46 days for controls, 60 days with temsirolimus, 71 days with cisplatin and 83 days with the combination. Median tumor weight was 402 mg, 178 mg, 259 mg and 123 mg respectively.
• The authors' conclusion: The authors concluded that temsirolimus is active against human MPM in vitro and in vivo, is especially active against cisplatin-resistant cells and synergizes with platinum chemotherapy. They suggested that mTOR inhibition be investigated further as a treatment strategy.
• Limitations the authors state:
  • The authors stated that the mechanisms behind the vulnerability of cisplatin-resistant cells to temsirolimus still need to be investigated.
  • The authors described the combination experiment in mice as an initial experiment.

Topics

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

Medical terms in this study, explained in our Lexicon: Pleural Mesothelioma, Chemotherapy, Immunohistochemistry, Cisplatin, Biphasic Mesothelioma, Sarcomatoid, Mesothelioma, Apoptosis.

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