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: (i) molecular targeted approaches, i.e. the inhibiton of vascular endothelial growth factor with Bevacizumab; (ii) immunotherapy with chimeric monoclonal antibody, immunotoxin, antibody drug conjugate, vaccine and viruses; (iii) inhibition of asbestos-induced inflammation, i.e. 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 vitro experimental models of mesothelioma revisited

“…MPM is a highly complex tumor at the genetic level lacking consistent molecular patterns that would inform on obvious treatment approaches, but which suggest there are multiple active oncogenic programs cooperating to drive this malignancy (14,15). To date, much of the new therapeutic approaches that have been tested in clinical trials have focused intervention efforts on one biological pathway or molecule that is deemed critical to the development and ongoing growth of MPM.…”

“…In the latest summaries (5,14,16), a current accepted view of MPM pathogenesis derives from in vitro studies of human and murine cells, in vivo murine models, as well as indirect evidence from human surgical or autopsy studies.…”

“…Multiple research efforts (small and multi-institutional groups) have been unable to convincingly detect SV40 genetic sequences in human MPM (21)(22)(23)(24)(25). Perhaps more notably, ongoing updates of MPM now have either omitted any further discussion of SV40 as a causative agent (14,16) or suggest that this viral contamination theory should be discarded (5 …”

“…A possible hypothesis to partly explain this characteristic would require multiple metachronous foci of mesothelial cells acquiring malignant growth, but direct evidence to explain this phenomenon is unavailable; (VII) Recent data indicates a polyclonal cell origin for MPM (36). This observation could explain clinical experience that recognizes MPM behaving as a composite of multiple tumors with interand intratumor genetic heterogeneity (14,16), contributing to the ability of MPM to generally resist all modes of therapy. But overall, the impact of this finding on MPM biology requires more investigation; (VIII) There are few consistent and highly recurrent genetic mutations acknowledged as oncogenic drivers despite a multitude of chromosomal and genetic MPM profiling studies (14,37).…”

Targeting the epigenome in malignant pleural mesothelioma

“…Malignant pleural mesotheliomas (MPM) are rare and highly lethal neoplasms attributable primarily to environmental or occupational exposure to asbestos and related fibers, influenced in some cases by predisposing germline mutations (1). Recent advances in "omics" technologies have enabled comprehensive gene and transcriptome analyses that have provided considerable insight regarding the pathogenesis, prognosis, and treatment of MPM (2,3).…”