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Novel insights into mesothelioma biology and implications for therapy

Key Points

  • Malignant mesothelioma is a universally lethal cancer that usually affects the pleura, and it is increasing in incidence worldwide. Carcinogenesis in this disease is unique in that the direct causal relationship between exposure to the causative environmental carcinogen, asbestos, and the development of mesothelioma is so well established.

  • Currently, platinum–antifolate combination chemotherapy remains the only established treatment, with pemetrexed and cisplatin combination chemotherapy the only licensed regimen. Here, despite tumour response rates of 45.5%, as well as improvements in progression-free survival of 6.1 months, overall survival of 13.3 months and cancer-related symptoms, benefits are usually modest at best and prognosis remains poor, with population-level survival estimated at approximately 8 months, as many patients are unfit for active treatment.

  • There has been recent exponential growth in our understanding of mesothelioma pathobiology, with an improvement in our knowledge of mesothelioma genetics, epigenetics, tumour microenvironment and immunobiology. The translational outputs from these data have now led to the discovery and development of promising therapeutic strategies.

  • Extensive interrogation of the mesothelioma genome has revealed the most frequent mutational events to involve tumour suppressor inactivation, mediated by multiple mechanisms, which include single nucleotide variation, copy number losses, gene fusions and splicing alterations. Tumour suppressors commonly inactivated include those encoded by cyclin-dependent kinase inhibitor 2A (CDKN2A), BRCA1 associated protein 1 (BAP1) and neurofibromin 2 (NF2).

  • There are now several promising novel antitumour agents under investigation in mesothelioma, including mesothelin-targeted therapies, arginine deprivation in arginosuccinate synthetase 1-deficient mesothelioma and immunotherapeutics such as immune checkpoint inhibitors.

Abstract

Malignant mesothelioma is a universally lethal cancer that is increasing in incidence worldwide. There is a dearth of effective therapies, with only one treatment (pemetrexed and cisplatin combination chemotherapy) approved in the past 13 years. However, the past 5 years have witnessed an exponential growth in our understanding of mesothelioma pathobiology, which is set to revolutionize therapeutic strategies. From a genomic standpoint, mesothelioma is characterized by a preponderance of tumour suppressor alterations, for which novel therapies are currently in development. Other promising antitumour agents include inhibitors against angiogenesis, mesothelin and immune checkpoints, which are at various phases of clinical trial testing.

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Figure 1: Timeline of research and legal milestones in mesothelioma research.
Figure 2: Mutational hierarchy in mesothelioma subtypes.
Figure 3: Inactivation of the Hippo pathway in mesothelioma.
Figure 4: Mesothelioma and the immune system.
Figure 5: Future molecular therapeutic targets in mesothelioma.

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Acknowledgements

S.P. acknowledges UK National Health Service funding to the Royal Marsden Hospital/Institute of Cancer Research NIHR-Biomedical Research Centre, London, UK.

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T.A.Y. is consultant to AstraZeneca, Roche, Pfizer, Bristol-Myers Squibb (BMS), EMD Serono, Clovis Oncology and Ignyta, Inc., has received research funding from AstraZeneca, Vertex and Clearbridge Biomedics, and has received travel support from AstraZeneca, GlaxoSmithKline, EMD Serono, Merck Sharp and Dohme (MSD) Oncology, Janssen-Cilag, Vertex and BMS. J.G.A. is consultant/speaker for AstraZeneca, Boehringer Ingelheim, Eli Lilly, MSD, BMS, Roche and Amphera, has received travel expenses from Pfizer, Merck, Boehringer Ingelheim, Verastem and Amphera, and has received research funding from Roche. S.P. is consultant to Ariad, AstraZeneca, Boehringer Ingelheim, BMS, Clovis Oncology, MSD, Novartis, Pfizer and Eli Lilly, has received honoraria from Boehringer Ingelheim, Pfizer and Eli Lilly, travel expenses from Boehringer Ingelheim, BMS, MSD and Pfizer, and research funding from Boehringer Ingelheim and Pierre Fabre. D.A.F. is consultant to Aduro, AstraZeneca, Bayer, Boehringer Ingelheim, Clovis, Medimmune, Lab 21, Lilly, Merck, Pierre Fabre, Roche-Genentech, member of speakers bureaux for BMS, Merck and AstraZeneca.

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Ongoing clinical trials in mesothelioma (PDF 149 kb)

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Glossary

Pleura

A serous membrane formed of a single layer of epithelium of mesothelial origin (mesothelial cells) that forms a closed invaginated sac (the pleural cavity), which contains a minimal amount of serous fluid and surrounds the lung. The pleural membrane reflection covering the surface of the lung is termed visceral pleura, and the reflection attached to the internal chest wall is termed the parietal pleura.

Asbestos

The generic commercial designation for a group of naturally occurring mineral silicate fibres.

Serpentine asbestos

Also known as white asbestos, this is an asbestos subclassification that consists of the mineral chrysotile.

Amphibole asbestos

Also known as brown and blue asbestos, this is an asbestos subclassification that consists of five minerals: actinolite and amosite (brown asbestos) and anthophyllite, crocidolite (blue asbestos) and tremolite.

Window of opportunity studies

Trials in which patients receive one or more novel antitumour agents between their cancer diagnosis and standard-of-care therapy (usually surgery). Tumour sampling is undertaken before and after therapy for translational research.

Ezrin, radixin and moesin (ERM) family

The ERM family proteins have structural and regulatory roles in the rearrangement of plasma membrane flexibility and protrusions through their reversible interaction with cortical actin filaments and plasma membrane. These ERM proteins are involved in cytoskeletal organization and offer a platform for the transmission of signals in response to various extracellular stimuli through their ability to crosslink transmembrane receptors with downstream signalling components.

Switch maintenance clinical trial

Treating a patient with a different drug immediately after that patient obtains maximal response to an initial induction therapy

Antimesothelin immunotoxin SS1P

(SS1(dsFv)PE38). A recombinant antimesothelin immunotoxin consisting of a mouse antimesothelin variable antibody fragment (Fv) linked to PE38, a truncated portion of Pseudomonas exotoxin A.

Antibody–drug conjugate

A monoclonal antibody attached to an antitumour agent by a chemical linker. This enables the unique targeting with a monoclonal antibody that has the cancer-killing ability of a cytotoxic drug and sensitive discrimination between normal and tumour tissue.

Antibody-dependent cell-mediated cytotoxicity

A mechanism of cell-mediated immune defence whereby an effector cell of the immune system actively lyses a target cell, whose membrane surface antigens have been bound by specific antibodies.

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Yap, T., Aerts, J., Popat, S. et al. Novel insights into mesothelioma biology and implications for therapy. Nat Rev Cancer 17, 475–488 (2017). https://doi.org/10.1038/nrc.2017.42

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