Latest developments in our understanding of the pathogenesis of mesothelioma and the design of targeted therapies

Our plain-English summary of Latest developments in our understanding of the pathogenesis of mesothelioma and the design of targeted therapies, by A. Bononi, A. Napolitano, H.I. Pass, et al (Expert Review of Respiratory Medicine, 2015).

The study

• Authors: A. Bononi, A. Napolitano, H.I. Pass, H. Yang, M. Carbone
• Journal: Expert Review of Respiratory Medicine
• Published: 2015;9(5):633-54
• Type of article: Review
• Cited by: 39 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Malignant mesothelioma is an aggressive cancer whose pathogenesis is causally linked to occupational exposure to asbestos. Familial clusters of mesotheliomas have been observed in settings of genetic predisposition. Mesothelioma incidence is anticipated to increase worldwide in the next two decades. Novel treatments are needed, as current treatment modalities may improve the quality of life, but have shown modest effects in improving overall survival. Increasing knowledge on the molecular characteristics of mesothelioma has led to the development of novel potential therapeutic strategies, including: molecular targeted approaches, that is the inhibition of vascular endothelial growth factor with bevacizumab; immunotherapy with chimeric monoclonal antibody, immunotoxin, antibody drug conjugate, vaccine and viruses; inhibition of asbestos-induced inflammation, that is aspirin inhibition of HMGB1 activity may decrease or delay mesothelioma onset and/or growth. We elaborate on the rationale behind new therapeutic strategies, and summarize available preclinical and clinical results, as well as efforts still ongoing.

In plain English

This article is a review. The authors summarized laboratory and clinical research on malignant pleural mesothelioma, which they described as causally linked to occupational asbestos exposure. It covered molecular targeted drugs, immunotherapy, and approaches against asbestos-induced inflammation. Among the cited results, two Phase III trials found that an antifolate drug (pemetrexed is one) plus cisplatin improved survival by about 11 weeks over cisplatin alone. Vorinostat did not improve overall survival in a Phase III trial of 660 pretreated patients. Adding bevacizumab to standard chemotherapy gave a median survival of 18.82 vs 16.07 months. The authors' own earlier work found somatic BAP1 mutations or inactivation in 63.6% of sporadic mesotheliomas. In a separate study by the authors, mice with a germline BAP1 mutation given low asbestos doses developed mesothelioma at a similar rate to wildtype mice given ten times higher doses. In the Physicians' Health Study, aspirin versus placebo gave a relative risk of mesothelioma of 0.7 (95% CI 0.3 to 1.9), based on 17 cases. The authors noted that this analysis lacked power for statistical significance. The authors concluded that anti-inflammatory therapies such as aspirin could prevent or delay mesothelioma in exposed people.

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 published and ongoing preclinical and clinical research, including the authors' own earlier studies
• Who was studied: Published laboratory, animal and clinical trial results on malignant pleural mesothelioma (MPM) and its treatment; the review focused on MPM rather than peritoneal mesothelioma
• Exposure: Asbestos in general, described as amphiboles (amosite, crocidolite, anthophyllite, actinolite, tremolite) and the serpentine chrysotile, and asbestos-induced inflammation; also other risk factors (erionite, antigorite, chest irradiation, germline BAP1 mutations)
• Main results:
  • Two cited Phase III trials: an antifolate (pemetrexed is one) plus cisplatin improved survival by about 11 weeks over cisplatin alone in MPM patients
  • Cited Phase III trial (VANTAGE 014): in 660 pretreated advanced MPM patients, vorinostat as second- or third-line therapy did not improve overall survival
  • Cited Phase III trial (IFCT-GFPC-0701 MAPS, presented at a 2015 meeting): patients given bevacizumab plus pemetrexed and cisplatin had median survival of 18.82 months vs 16.07 months for those without bevacizumab, p = 0.0127
  • Authors' earlier work on human tumors: 63.6% of sporadic mesotheliomas contained somatic BAP1 mutations or inactivation
  • Authors' separate earlier mouse study (reference 76): mice with germline BAP1 mutations exposed to low asbestos doses developed mesothelioma at a rate similar to wildtype mice exposed to ten times higher doses
  • The authors reported that, to date, none of the mesothelioma patients they found carrying germline BAP1 mutations had been professionally exposed to asbestos
  • Cited KEYNOTE-028 trial: in mesothelioma patients, the response rate to pembrolizumab was 28%, and another 48% had stable disease
  • Cited Physicians' Health Study: 22,067 physicians were followed for 24 years, with 17 mesothelioma cases. Aspirin (325 mg on alternate days) versus placebo gave a relative risk of 0.7 (95% CI 0.3 to 1.9)
  • The authors summarized that molecular therapies had so far not improved average survival of mesothelioma patients
• The authors' conclusion: The authors concluded that, given the decades-long latency, therapies that reduce chronic inflammation, such as aspirin, could prevent or delay carcinogenesis in exposed individuals. They also stated that BAP1 is the most promising driver gene and that they plan to test aspirin's effect on mesothelioma onset.
• Limitations the authors state:
  • The Physicians' Health Study had too few mesothelioma cases to give a statistically significant result
  • The authors noted that, as far as they knew, possible therapeutic effects of aspirin in mesothelioma had not been studied

Topics

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

Medical terms in this study, explained in our Lexicon: Mesothelioma, Malignant Mesothelioma, Occupational Exposure, Quality of Life, Overall Survival, Bevacizumab, Immunotherapy, Monoclonal Antibody.

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• Chemotherapy and targeted therapies for unresectable malignant mesothelioma — R.J. Kelly, E. Sharon, et al. (2011)
• Immune therapies for malignant mesothelioma — S.A. Antoniu, G. Dimofte, et al. (2014)
• Systemic approach to malignant pleural mesothelioma: what news of chemotherapy, targeted agents and immunotherapy? — D. Signorelli, M. Macerelli, et al. (2016)
• New insights into understanding the mechanisms, pathogenesis, and management of malignant mesotheliomas — B.T. Mossman, A. Shukla, et al. (2013)

Browse more research in Expert Review of Respiratory Medicine, or return to medical research.