Biological basis for novel mesothelioma therapies

Our plain-English summary of Biological basis for novel mesothelioma therapies, by J. Obacz, H. Yung, M. Shamseddin, et al (British Journal of Cancer, 2021).

The study

• Authors: J. Obacz, H. Yung, M. Shamseddin, E. Linnane, X. Liu, A.A. Azad, D.M. Rassl, D. Fairen-Jimenez, R.C. Rintoul, M.Z. Nikolić, S.J. Marciniak
• Journal: British Journal of Cancer
• Published: 2021;125(8):1039-1055
• Type of article: Review
• Cited by: 18 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Mesothelioma is an aggressive cancer that is associated with exposure to asbestos. Although asbestos is banned in several countries, including the UK, an epidemic of mesothelioma is predicted to affect middle-income countries during this century owing to their heavy consumption of asbestos. The prognosis for patients with mesothelioma is poor, reflecting a failure of conventional chemotherapy that has ultimately resulted from an inadequate understanding of its biology. However, recent work has revolutionised the study of mesothelioma, identifying genetic and pathophysiological vulnerabilities, including the loss of tumour suppressors, epigenetic dysregulation and susceptibility to nutrient stress. We discuss how this knowledge, combined with advances in immunotherapy, is enabling the development of novel targeted therapies.

© 2021. The Author(s).

In plain English

This was a review article, not a new study. It discussed mesothelioma biology and summarised past and ongoing clinical trials of new treatments, focusing on pleural mesothelioma. The authors described asbestos as a frequent cause. Cited studies found that tumour suppressor genes such as CDKN2A, BAP1 and NF2 are frequently affected, and that inherited (germline) BAP1 mutations predispose to the disease. A phase III vorinostat trial in 650 patients showed no overall survival improvement, and a phase II defactinib trial in 344 patients showed no improvement in disease outcome. In a phase III trial of 448 patients, adding bevacizumab raised median overall survival from 16.1 to 18.8 months. In the CheckMate 743 trial in unresectable mesothelioma, nivolumab plus ipilimumab significantly improved overall survival compared with chemotherapy, predominantly in non-epithelioid disease, and 2-year survival was 41% versus 27%. The authors concluded that prognosis remains poor. They noted that treatments that look promising early often fail in phase III trials, possibly because the patients most likely to benefit were not pre-selected, and that there is cause for optimism.

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: Narrative review of mesothelioma biology and of completed and ongoing clinical trials of new therapies
• Who was studied: No new patients were studied. The review covered published laboratory, animal and clinical studies and listed clinical trials, mainly in pleural mesothelioma.
• Exposure: Asbestos was described as a frequent cause of mesothelioma, along with other possible triggers (long, straight carbon nanotubes, genetic predisposition, radiation therapy). No specific fiber types were named. The review's main subject was treatments, not exposure.
• Main results:
  • Studies cited in the review report that tumour suppressor genes including CDKN2A, BAP1 and NF2 are frequently affected in mesothelioma.
  • The review cites work showing that germline BAP1 mutations predispose to malignant mesothelioma. Together with other pathogenic mutations linked to cancer, these were reported to account for 12% of all cases.
  • Cited trial: a phase III trial of vorinostat in 650 patients with mesothelioma showed no improvement in overall survival.
  • Cited trial: in a phase II trial of defactinib in 344 patients with mesothelioma and low levels of Merlin, no improvement in disease outcome was observed.
  • Cited trial: in the phase III MAPS trial of 448 patients, adding bevacizumab increased median overall survival from 16.1 to 18.8 months.
  • Cited trial: in the CheckMate 743 phase III trial in unresectable mesothelioma, nivolumab plus ipilimumab significantly improved overall survival compared with chemotherapy, predominantly in non-epithelioid disease (18.1 versus 14.1 months as printed). Two-year overall survival was 41% with nivolumab plus ipilimumab and 27% with chemotherapy.
  • As reported in the review, median survival was 4 months for sarcomatoid mesothelioma, compared with 13.1 months for epithelioid and 8.4 months for biphasic mesothelioma.
• The authors' conclusion: The authors concluded that prognosis remains poor and that targeted therapies and immunotherapies which show promise early often fail in phase III trials. In their view this might reflect a failure to pre-select the patients most likely to benefit, and better personalisation of treatment might help. They also stated there is cause for optimism.
• Limitations the authors state:
  • The authors noted a gap in the available research: most studies have focused on epithelioid mesothelioma, with relatively few on the sarcomatoid subtype.
  • The authors noted that several large immunotherapy trials had yet to report their data.

Topics

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

Medical terms in this study, explained in our Lexicon: Mesothelioma, Prognosis, Chemotherapy, Immunotherapy.

Related studies

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• Novel functional view of the crocidolite asbestos-treated A549 human lung epithelial transcriptome reveals an intricate network of pathways with opposing functions — J.M. Hevel, L.C. Olson-Buelow, et al. (2008)
• Novel intrapleural therapies for malignant diseases — A.R. Haas, D.H. Sterman (2012)
• Malignant pleural mesothelioma: update on treatment options with a focus on novel therapies — A.R. Haas, D.H. Sterman (2013)
• Emerging biological therapies for the treatment of malignant pleural mesothelioma — A.P. Davis, S.C. Kao, et al. (2021)
• How asbestos drives the tissue towards tumors: YAP activation, macrophage and mesothelial precursor recruitment, RNA editing, and somatic mutations — H. Rehrauer, L. Wu, et al. (2018)

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