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

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.

Keywords:

• asbestos
• aspirin
• BAP1
• carcinogenesis
• HMGB1
• immunotherapy
• mesothelioma
• molecular therapy
• polyclonal tumors

Financial & competing interests disclosure

This work was supported by NCI 1R01 CA198138-01, NCI R01 CA106567, NCI P01 CA114047 and NCI P30 CA071789 received by M. Carbone, by NCI R01 CA160715-0A, DOD CA120355, and The Riviera United 4-a Cure received by H.Y, by the V-Foundation to M Carbone and H Yang and by the University of Hawai’i Foundation, which received donations to support mesothelioma research from Honeywell International Inc., to M Carbone. The University of Hawaii has filed for patents on HMGB1 and mesothelioma, on which M Carbone, H Yang and HI Pass are the inventors. M Carbone has pending patent applications on BAP1 and provides consultation for mesothelioma expertise and diagnosis. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Key issues

• MM is a very aggressive tumor that arises from mesothelial cells of the pleural, pericardial and peritoneal cavities. Patients are usually diagnosed at advanced stages and the prognosis is very poor, with a median survival of 6–12 months and a 5-year survival of <5% [240].

• MM incidence is still increasing worldwide and is not expected to fall off in the next two decades [1,10].

• Most MPM patients have unresectable disease and are treated with palliative combination chemotherapy (cisplatin and pemetrexed is the first-line treatment approved by the US FDA). However, MPM is largely unresponsive to conventional therapy and the minority of patients that initially respond to therapy eventually become resistant [36].

• MPM is often associated with asbestos exposure. Asbestos carcinogenesis is linked to chronic inflammation that may lead to malignant mesothelial cell transformation after decades long latency [15,18,240].

• Novel strategies that interfere with asbestos-mediated inflammation might prevent or delay the onset of MM. HMGB1 is a candidate target for anti-inflammatory therapy and a potential marker of exposure to carcinogenic mineral fibers [16]. Aspirin is an FDA-approved candidate drug that targets HMGB1, and this drug taken in daily amounts of 85–375 mg has conclusively shown the ability to decrease the incidence of colon cancer and of other inflammation-related malignancies. Similarly, individuals exposed to asbestos and at risk of developing MM may benefit from daily doses of aspirin [246]. Also reactivation of the immune system against cancer cells via immune checkpoint inhibitors has shown significant clinical results.

• People have different genetic susceptibilities to asbestos and to MM development. Germline BAP1 mutations are present in families with a high incidence of MM [24]. BAP1 somatic mutations have also been found in >60% of sporadic MM, pointing at BAP1 as the most commonly mutated gene in this malignancy [48]. Genetic testing for BAP1 mutations should help in the identification of genetically susceptible individuals who have the highest risk of developing MM.

• Germline BAP1 mutations predispose to the tumorigenic effect of asbestos, possibly because of a deregulated inflammatory response. Care of individuals carrying germline BAP1 mutations should consider reducing exposure of to even minimal sources of carcinogenic fibers and a preventive therapy to target the inflammatory response [76].

• The polyclonal origin of MM complicates attempts to develop molecular therapies [38]. Future treatment strategies should not be based on monotherapy, but should comprise multisite and multimodal treatment, if such treatment can be developed without the present toxic effects.

Notes