Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

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.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

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.

Similar content being viewed by others

References

  1. Bianchi, C. & Bianchi, T. Malignant mesothelioma: global incidence and relationship with asbestos. Ind. Health 45, 379–387 (2007).

    PubMed  Google Scholar 

  2. Mutsaers, S. E. The mesothelial cell. Int. J. Biochem. Cell Biol. 36, 9–16 (2004).

    CAS  PubMed  Google Scholar 

  3. Wagner, J. C., Sleggs, C. A. & Marchand, P. Diffuse pleural mesothelioma and asbestos exposure in the North Western Cape Province. Br. J. Ind. Med. 17, 260–271 (1960).

    CAS  PubMed  PubMed Central  Google Scholar 

  4. Carbone, M. et al. Malignant mesothelioma: facts, myths, and hypotheses. J. Cell. Physiol. 227, 44–58 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  5. Farioli, A. et al. Radiation-induced mesothelioma among long-term solid cancer survivors: a longitudinal analysis of SEER database. Cancer Med. 5, 950–959 (2016).

    PubMed  PubMed Central  Google Scholar 

  6. Peto, J., Hodgson, J. T., Matthews, F. E. & Jones, J. R. Continuing increase in mesothelioma mortality in Britain. Lancet 345, 535–539 (1995).

    CAS  PubMed  Google Scholar 

  7. Pott, F. et al. Carcinogenicity studies on fibres, metal compounds, and some other dusts in rats. Exp. Pathol. 32, 129–152 (1987).

    CAS  PubMed  Google Scholar 

  8. Boutin, C. & Rey, F. Thoracoscopy in pleural malignant mesothelioma: a prospective study of 188 consecutive patients. Part 1: diagnosis. Cancer 72, 389–393 (1993).

    CAS  PubMed  Google Scholar 

  9. Choe, N., Tanaka, S. & Kagan, E. Asbestos fibers and interleukin-1 upregulate the formation of reactive nitrogen species in rat pleural mesothelial cells. Am. J. Respir. Cell Mol. Biol. 19, 226–236 (1998).

    CAS  PubMed  Google Scholar 

  10. Huang, S. X., Jaurand, M. C., Kamp, D. W., Whysner, J. & Hei, T. K. Role of mutagenicity in asbestos fiber-induced carcinogenicity and other diseases. J. Toxicol. Environ. Health B Crit. Rev. 14, 179–245 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  11. Zanella, C. L., Posada, J., Tritton, T. R. & Mossman, B. T. Asbestos causes stimulation of the extracellular signal-regulated kinase 1 mitogen-activated protein kinase cascade after phosphorylation of the epidermal growth factor receptor. Cancer Res. 56, 5334–5338 (1996).

    CAS  PubMed  Google Scholar 

  12. Marzo, A. L., Fitzpatrick, D. R., Robinson, B. W. & Scott, B. Antisense oligonucleotides specific for transforming growth factor beta2 inhibit the growth of malignant mesothelioma both in vitro and in vivo. Cancer Res. 57, 3200–3207 (1997).

    CAS  PubMed  Google Scholar 

  13. Yang, H. et al. Programmed necrosis induced by asbestos in human mesothelial cells causes high-mobility group box 1 protein release and resultant inflammation. Proc. Natl Acad. Sci. USA 107, 12611–12616 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  14. Qi, F. et al. Continuous exposure to chrysotile asbestos can cause transformation of human mesothelial cells via HMGB1 and TNF-alpha signaling. Am. J. Pathol. 183, 1654–1666 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Attanoos, R. L. & Gibbs, A. R. Pathology of malignant mesothelioma. Histopathology 30, 403–418 (1997).

    CAS  PubMed  Google Scholar 

  16. Travis, W. D., Brambilla, E., Burke, A., Marx, A. & Nicholson, A. G. WHO Classification of Tumours of the Lung, Pleura, Thymus and Heart (WHO, 2015).

    Google Scholar 

  17. Kao, S. C. et al. Accuracy of diagnostic biopsy for the histological subtype of malignant pleural mesothelioma. J. Thorac. Oncol. 6, 602–605 (2011).

    PubMed  Google Scholar 

  18. Comertpay, S. et al. Evaluation of clonal origin of malignant mesothelioma. J. Transl Med. 12, 301 (2014).

    PubMed  PubMed Central  Google Scholar 

  19. National Lung Cancer Audit. National Lung Cancer Audit Report 2014: Mesothelioma Report for the Period 2008–2012 (Health and Social Care Information Centre, 2014).

  20. American Cancer Society. Survival statistics for mesothelioma. Cancer.org http://www.cancer.org/cancer/malignantmesothelioma/detailedguide/malignant-mesothelioma-survival-statistics (2016).

  21. Fennell, D. A. et al. Statistical validation of the EORTC prognostic model for malignant pleural mesothelioma based on three consecutive phase II trials. J. Clin. Oncol. 23, 184–189 (2005).

    PubMed  Google Scholar 

  22. van Meerbeeck, J. P. et al. Randomized phase III study of cisplatin with or without raltitrexed in patients with malignant pleural mesothelioma: an intergroup study of the European Organisation for Research and Treatment of Cancer Lung Cancer Group and the National Cancer Institute of Canada. J. Clin. Oncol. 23, 6881–6889 (2005).

    CAS  PubMed  Google Scholar 

  23. Vogelzang, N. J. et al. Phase III study of pemetrexed in combination with cisplatin versus cisplatin alone in patients with malignant pleural mesothelioma. J. Clin. Oncol. 21, 2636–2644 (2003). Key phase III trial confirming pemetrexed plus cisplatin as standard of care in mesothelioma.

    CAS  PubMed  Google Scholar 

  24. Treasure, T. et al. Extra-pleural pneumonectomy versus no extra-pleural pneumonectomy for patients with malignant pleural mesothelioma: clinical outcomes of the Mesothelioma and Radical Surgery (MARS) randomised feasibility study. Lancet Oncol. 12, 763–772 (2011).

    PubMed  PubMed Central  Google Scholar 

  25. US National Library of Medicine. ClinicalTrials.gov https://www.clinicaltrials.gov/ct2/show/NCT02040272 (2017).

  26. Zalcman, G. et al. Bevacizumab for newly diagnosed pleural mesothelioma in the Mesothelioma Avastin Cisplatin Pemetrexed Study (MAPS): a randomised, controlled, open-label, phase 3 trial. Lancet 387, 1405–1414 (2016). Phase III MAPS trial demonstrating patient benefit with bevacizumab plus chemotherapy in mesothelioma.

    CAS  PubMed  Google Scholar 

  27. US National Library of Medicine. ClinicalTrials.gov http://www.clinicaltrials.gov/ct2/show/NCT02991482 (2017).

  28. US National Library of Medicine. ClinicalTrials.gov http://www.clinicaltrials.gov/ct2/show/NCT02784171 (2017).

  29. US National Library of Medicine. ClinicalTrials.gov http://www.clinicaltrials.gov/ct2/show/NCT02628067 (2017).

  30. US National Library of Medicine. ClinicalTrials.gov http://www.clinicaltrials.gov/ct2/show/NCT03063450 (2017).

  31. US National Library of Medicine. ClinicalTrials.gov http://www.clinicaltrials.gov/ct2/show/NCT02716272 (2016).

  32. US National Library of Medicine. ClinicalTrials.gov http://www.clinicaltrials.gov/ct2/show/NCT02899299 (2017).

  33. Bronte, G. et al. The resistance related to targeted therapy in malignant pleural mesothelioma: why has not the target been hit yet? Crit. Rev. Oncol. Hematol. 107, 20–32 (2016).

    PubMed  Google Scholar 

  34. Cheng, L. et al. Response evaluation in mesothelioma: beyond RECIST. Lung Cancer 90, 433–441 (2015).

    PubMed  Google Scholar 

  35. Papadatos-Pastos, D. et al. Clinical outcomes and prognostic factors of patients with advanced mesothelioma treated in a phase I clinical trials unit. Eur. J. Cancer 75, 56–62 (2017).

    PubMed  Google Scholar 

  36. Bueno, R. et al. Comprehensive genomic analysis of malignant pleural mesothelioma identifies recurrent mutations, gene fusions and splicing alterations. Nat. Genet. 48, 407–416 (2016). Important study detailing comprehensive genomic analysis of malignant pleural mesothelioma.

    CAS  PubMed  Google Scholar 

  37. Guo, G. et al. Whole-exome sequencing reveals frequent genetic alterations in BAP1, NF2, CDKN2A, and CUL1 in malignant pleural mesothelioma. Cancer Res. 75, 264–269 (2015).

    CAS  PubMed  Google Scholar 

  38. Lo Iacono, M. et al. Targeted next-generation sequencing of cancer genes in advanced stage malignant pleural mesothelioma: a retrospective study. J. Thorac. Oncol. 10, 492–499 (2015).

    CAS  PubMed  Google Scholar 

  39. Ugurluer, G. et al. Genome-based mutational analysis by next generation sequencing in patients with malignant pleural and peritoneal mesothelioma. Anticancer Res. 36, 2331–2338 (2016).

    CAS  PubMed  Google Scholar 

  40. Christensen, B. C. et al. Integrated profiling reveals a global correlation between epigenetic and genetic alterations in mesothelioma. Cancer Res. 70, 5686–5694 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  41. Christensen, B. C. et al. Epigenetic profiles distinguish pleural mesothelioma from normal pleura and predict lung asbestos burden and clinical outcome. Cancer Res. 69, 227–234 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  42. Jamal-Hanjani, M. et al. Tracking genomic cancer evolution for precision medicine: the lung TRACERx study. PLoS Biol. 12, e1001906 (2014).

    PubMed  PubMed Central  Google Scholar 

  43. Cheng, J. Q. et al. p16 alterations and deletion mapping of 9p21-p22 in malignant mesothelioma. Cancer Res. 54, 5547–5551 (1994).

    CAS  PubMed  Google Scholar 

  44. Xio, S. et al. Codeletion of p15 and p16 in primary malignant mesothelioma. Oncogene 11, 511–515 (1995).

    CAS  PubMed  Google Scholar 

  45. Wong, L., Zhou, J., Anderson, D. & Kratzke, R. A. Inactivation of p16INK4a expression in malignant mesothelioma by methylation. Lung Cancer 38, 131–136 (2002).

    PubMed  Google Scholar 

  46. Christensen, B. C. et al. Asbestos exposure predicts cell cycle control gene promoter methylation in pleural mesothelioma. Carcinogenesis 29, 1555–1559 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  47. Singhi, A. D. et al. The prognostic significance of BAP1, NF2, and CDKN2A in malignant peritoneal mesothelioma. Mod. Pathol. 29, 14–24 (2016).

    CAS  PubMed  Google Scholar 

  48. Jongsma, J. et al. A conditional mouse model for malignant mesothelioma. Cancer Cell 13, 261–271 (2008). Study detailing the generation of a conditional mouse model to further dissect crucial pathways in mesothelioma development and progression; this model serves as an invaluable tool to test new intervention strategies.

    CAS  PubMed  Google Scholar 

  49. Lopez-Rios, F. et al. Global gene expression profiling of pleural mesotheliomas: overexpression of aurora kinases and P16/CDKN2A deletion as prognostic factors and critical evaluation of microarray-based prognostic prediction. Cancer Res. 66, 2970–2979 (2006).

    CAS  PubMed  Google Scholar 

  50. Dacic, S. et al. Prognostic significance of p16/cdkn2a loss in pleural malignant mesotheliomas. Virchows Arch. 453, 627–635 (2008).

    PubMed  Google Scholar 

  51. Ivanov, S. V. et al. Genomic events associated with progression of pleural malignant mesothelioma. Int. J. Cancer 124, 589–599 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  52. Jennings, C. J. et al. Differential p16/INK4A cyclin-dependent kinase inhibitor expression correlates with chemotherapy efficacy in a cohort of 88 malignant pleural mesothelioma patients. Br. J. Cancer 113, 69–75 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  53. De Rienzo, A. et al. Gender-specific molecular and clinical features underlie malignant pleural mesothelioma. Cancer Res. 76, 319–328 (2016).

    CAS  PubMed  Google Scholar 

  54. Serrano, M. et al. Role of the INK4a locus in tumor suppression and cell mortality. Cell 85, 27–37 (1996).

    CAS  PubMed  Google Scholar 

  55. Pomerantz, J. et al. The Ink4a tumor suppressor gene product, p19Arf, interacts with MDM2 and neutralizes MDM2's inhibition of p53. Cell 92, 713–723 (1998).

    CAS  PubMed  Google Scholar 

  56. Zhang, Y., Xiong, Y. & Yarbrough, W. G. ARF promotes MDM2 degradation and stabilizes p53: ARF-INK4a locus deletion impairs both the Rb and p53 tumor suppression pathways. Cell 92, 725–734 (1998).

    CAS  PubMed  Google Scholar 

  57. Oliner, J. D. et al. Oncoprotein MDM2 conceals the activation domain of tumour suppressor p53. Nature 362, 857–860 (1993).

    CAS  PubMed  Google Scholar 

  58. Stott, F. J. et al. The alternative product from the human CDKN2A locus, p14ARF, participates in a regulatory feedback loop with p53 and MDM2. EMBO J. 17, 5001–5014 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  59. Montes de Oca Luna, R., Wagner, D. S. & Lozano, G. Rescue of early embryonic lethality in mdm2-deficient mice by deletion of p53. Nature 378, 203–206 (1995).

    CAS  PubMed  Google Scholar 

  60. Urso, L., Calabrese, F., Favaretto, A., Conte, P. & Pasello, G. Critical review about MDM2 in cancer: possible role in malignant mesothelioma and implications for treatment. Crit. Rev. Oncol. Hematol. 97, 220–230 (2016).

    PubMed  Google Scholar 

  61. Walter, R. F. et al. MDM2 is an important prognostic and predictive factor for platin–pemetrexed therapy in malignant pleural mesotheliomas and deregulation of P14/ARF (encoded by CDKN2A) seems to contribute to an MDM2-driven inactivation of P53. Br. J. Cancer 112, 883–890 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  62. Sui, G. et al. Yin Yang 1 is a negative regulator of p53. Cell 117, 859–872 (2004).

    CAS  PubMed  Google Scholar 

  63. Frizelle, S. P. et al. Inhibition of both mesothelioma cell growth and Cdk4 activity following treatment with a TATp16INK4a peptide. Anticancer Res. 28, 1–7 (2008).

    CAS  PubMed  Google Scholar 

  64. Frizelle, S. P. et al. Re-expression of p16INK4a in mesothelioma cells results in cell cycle arrest, cell death, tumor suppression and tumor regression. Oncogene 16, 3087–3095 (1998).

    CAS  PubMed  Google Scholar 

  65. Eilers, G. et al. CDKN2A/p16 loss implicates CDK4 as a therapeutic target in imatinib-resistant dermatofibrosarcoma protuberans. Mol. Cancer Ther. 14, 1346–1353 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  66. Huang, S. et al. CDK4/6 inhibitor suppresses gastric cancer with CDKN2A mutation. Int. J. Clin. Exp. Med. 8, 11692–11700 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  67. Konecny, G. E. et al. Expression of p16 and retinoblastoma determines response to CDK4/6 inhibition in ovarian cancer. Clin. Cancer Res. 17, 1591–1602 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  68. Wiedemeyer, W. R. et al. Pattern of retinoblastoma pathway inactivation dictates response to CDK4/6 inhibition in GBM. Proc. Natl Acad. Sci. USA 107, 11501–11506 (2010).

    PubMed  PubMed Central  Google Scholar 

  69. Kadariya, Y. et al. Bap1 is a bona fide tumor suppressor: genetic evidence from mouse models carrying heterozygous germline Bap1 mutations. Cancer Res. 76, 2836–2844 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  70. Dey, A. et al. Loss of the tumor suppressor BAP1 causes myeloid transformation. Science 337, 1541–1546 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  71. Testa, J. R. et al. Germline BAP1 mutations predispose to malignant mesothelioma. Nat. Genet. 43, 1022–1025 (2011). Important study describing germline BAP1 mutations in mesothelioma.

    CAS  PubMed  PubMed Central  Google Scholar 

  72. Bott, M. et al. The nuclear deubiquitinase BAP1 is commonly inactivated by somatic mutations and 3p21.1 losses in malignant pleural mesothelioma. Nat. Genet. 43, 668–672 (2011). Important study describing somatic inactivating BAP1 mutations in mesothelioma.

    CAS  PubMed  PubMed Central  Google Scholar 

  73. Yoshikawa, Y. et al. High-density array-CGH with targeted NGS unmask multiple noncontiguous minute deletions on chromosome 3p21 in mesothelioma. Proc. Natl Acad. Sci. USA 113, 13432–13437 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  74. Jensen, D. E. et al. BAP1: a novel ubiquitin hydrolase which binds to the BRCA1 RING finger and enhances BRCA1-mediated cell growth suppression. Oncogene 16, 1097–1112 (1998).

    CAS  PubMed  Google Scholar 

  75. Yu, H. et al. Tumor suppressor and deubiquitinase BAP1 promotes DNA double-strand break repair. Proc. Natl Acad. Sci. USA 111, 285–290 (2014).

    CAS  PubMed  Google Scholar 

  76. Ismail, I. H. et al. Germline mutations in BAP1 impair its function in DNA double-strand break repair. CancerRes. 74, 4282–4294 (2014).

    CAS  Google Scholar 

  77. Hakiri, S. et al. Functional differences between wild-type and mutant-type BRCA1-associated protein 1 tumor suppressor against malignant mesothelioma cells. Cancer Sci. 106, 990–999 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  78. Kemp, C. D. et al. Polycomb repressor complex-2 is a novel target for mesothelioma therapy. Clin. Cancer Res. 18, 77–90 (2012).

    CAS  PubMed  Google Scholar 

  79. LaFave, L. M. et al. Loss of BAP1 function leads to EZH2-dependent transformation. Nat. Med. 21, 1344–1349 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  80. US National Library of Medicine. ClinicalTrials.gov http://www.clinicaltrials.gov/ct2/show/NCT02860286 (2017).

  81. Bianchi, A. B. et al. High frequency of inactivating mutations in the neurofibromatosis type 2 gene (NF2) in primary malignant mesotheliomas. Proc. Natl Acad. Sci. USA 92, 10854–10858 (1995). Interesting study demonstrating high frequency of inactivating mutations in NF2 in mesothelioma.

    CAS  PubMed  PubMed Central  Google Scholar 

  82. Sekido, Y. et al. Neurofibromatosis type 2 (NF2) gene is somatically mutated in mesothelioma but not in lung cancer. Cancer Res. 55, 1227–1231 (1995).

    CAS  PubMed  Google Scholar 

  83. Li, W. et al. Merlin/NF2 suppresses tumorigenesis by inhibiting the E3 ubiquitin ligase CRL4DCAF1 in the nucleus. Cell 140, 477–490 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  84. Mizuno, T. et al. YAP induces malignant mesothelioma cell proliferation by upregulating transcription of cell cycle-promoting genes. Oncogene 31, 5117–5122 (2012).

    CAS  PubMed  Google Scholar 

  85. Yu, F. X., Zhao, B. & Guan, K. L. Hippo pathway in organ size control, tissue homeostasis, and cancer. Cell 163, 811–828 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  86. Yokoyama, T. et al. YAP1 is involved in mesothelioma development and negatively regulated by Merlin through phosphorylation. Carcinogenesis 29, 2139–2146 (2008).

    CAS  PubMed  Google Scholar 

  87. Miyanaga, A. et al. Hippo pathway gene mutations in malignant mesothelioma: revealed by RNA and targeted exon sequencing. J. Thorac. Oncol. 10, 844–851 (2015).

    CAS  PubMed  Google Scholar 

  88. Murakami, H. et al. LATS2 is a tumor suppressor gene of malignant mesothelioma. Cancer Res. 71, 873–883 (2011).

    CAS  PubMed  Google Scholar 

  89. Cheng, J. Q. et al. Frequent mutations of NF2 and allelic loss from chromosome band 22q12 in malignant mesothelioma: evidence for a two-hit mechanism of NF2 inactivation. Genes Chromosomes Cancer 24, 238–242 (1999).

    CAS  PubMed  Google Scholar 

  90. Altomare, D. A. et al. A mouse model recapitulating molecular features of human mesothelioma. Cancer Res. 65, 8090–8095 (2005).

    CAS  PubMed  Google Scholar 

  91. Fleury-Feith, J. et al. Hemizygosity of Nf2 is associated with increased susceptibility to asbestos-induced peritoneal tumours. Oncogene 22, 3799–3805 (2003).

    CAS  PubMed  Google Scholar 

  92. Poulikakos, P. I. et al. Re-expression of the tumor suppressor NF2/merlin inhibits invasiveness in mesothelioma cells and negatively regulates FAK. Oncogene 25, 5960–5968 (2006).

    CAS  PubMed  Google Scholar 

  93. Shapiro, I. M. et al. Merlin deficiency predicts FAK inhibitor sensitivity: a synthetic lethal relationship. Sci. Transl Med. 6, 237ra68 (2014). Important study showing synthetic lethal relationship between Merlin and FAK.

    PubMed  PubMed Central  Google Scholar 

  94. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT01870609 (2017).

  95. Bueno, R. et al. Phase 2 neoadjuvant study of VX-6063, a FAK inhibitor, in subjects with surgically resectable malignant pleural mesothelioma [abstract]. Presented at 13th International Conference of the International Mesothelioma Interest Group 2016 MS10.04 (2016).

  96. Zhou, S. et al. Multipoint targeting of the PI3K/mTOR pathway in mesothelioma. Br. J. Cancer 110, 2479–2488 (2014). Study rationalizing targeting of the PI3K–AKT pathway in mesothelioma.

    CAS  PubMed  PubMed Central  Google Scholar 

  97. Dolly, S. O. et al. Phase I study of apitolisib (GDC-0980), dual phosphatidylinositol-3-kinase and mammalian target of rapamycin kinase inhibitor, in patients with advanced solid tumors. Clin. Cancer Res. 22, 2874–2884 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  98. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT01655225 (2017).

  99. Yap, T. A., Omlin, A. & de Bono, J. S. Development of therapeutic combinations targeting major cancer signaling pathways. J. Clin. Oncol. 31, 1592–1605 (2013).

    CAS  PubMed  Google Scholar 

  100. Sundar, R., Valeri, N., Harrington, K. J. & Yap, T. A. Combining molecularly targeted agents: is more always better? Clin. Cancer Res. 23, 1123–1125 (2017).

    CAS  PubMed  Google Scholar 

  101. Harris, S. J., Brown, J., Lopez, J. & Yap, T. A. Immuno-oncology combinations: raising the tail of the survival curve. Cancer Biol. Med. 13, 171–193 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  102. Soria, J. C., Massard, C. & Izzedine, H. From theoretical synergy to clinical supra-additive toxicity. J. Clin. Oncol. 27, 1359–1361 (2009).

    CAS  PubMed  Google Scholar 

  103. Pastan, I. & Hassan, R. Discovery of mesothelin and exploiting it as a target for immunotherapy. Cancer Res. 74, 2907–2912 (2014). Important review on the role of mesothelin in mesothelioma.

    CAS  PubMed  PubMed Central  Google Scholar 

  104. Hassan, R. et al. Phase 1 study of the antimesothelin immunotoxin SS1P in combination with pemetrexed and cisplatin for front-line therapy of pleural mesothelioma and correlation of tumor response with serum mesothelin, megakaryocyte potentiating factor, and cancer antigen 125. Cancer 120, 3311–3319 (2014).

    CAS  PubMed  Google Scholar 

  105. Hassan, R. et al. Major cancer regressions in mesothelioma after treatment with an anti-mesothelin immunotoxin and immune suppression. Sci. Transl Med. 5, 208ra147 (2013).

    PubMed  PubMed Central  Google Scholar 

  106. Hassan, R. et al. Preclinical evaluation of MORAb-009, a chimeric antibody targeting tumor-associated mesothelin. Cancer Immun. 7, 20 (2007).

    PubMed  PubMed Central  Google Scholar 

  107. Kaneko, O. et al. A binding domain on mesothelin for CA125/MUC16. J. Biol. Chem. 284, 3739–3749 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  108. Hassan, R. et al. Phase II clinical trial of amatuximab, a chimeric antimesothelin antibody with pemetrexed and cisplatin in advanced unresectable pleural mesothelioma. Clin. Cancer Res. 20, 5927–5936 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  109. Hassan, R. et al. A randomized, placebo-controlled study of amatuximab in combination with pemetrexed and cisplatin (P/C) as front-line therapy for subjects with malignant pleural mesothelioma (MPM) [abstract]. J. Clin. Oncol. 34 (Suppl.), TPS8577 (2016).

    Google Scholar 

  110. Golfier, S. et al. Anetumab ravtansine: a novel mesothelin-targeting antibody–drug conjugate cures tumors with heterogeneous target expression favored by bystander effect. Mol. Cancer Ther. 13, 1537–1548 (2014).

    CAS  PubMed  Google Scholar 

  111. Blumenschein, G. R. et al. Phase I study of anti-mesothelin antibody drug conjugate anetumab ravtansine (AR) [abstract]. J. Clin. Oncol. 34 (Suppl.), 2509 (2016).

    Google Scholar 

  112. Hassan, R. et al. A pivotal randomized phase II study of anetumab ravtansine or vinorelbine in patients with advanced or metastatic pleural mesothelioma after progression on platinum/pemetrexed-based chemotherapy (NCT02610140) [abstract]. J. Clin. Oncol. 34 (Suppl.), TPS8576 (2016).

    Google Scholar 

  113. US National Library of Medicine. ClinicalTrials.gov http://www.clinicaltrials.gov/ct2/show/NCT02610140 (2017).

  114. Mavrakis, K. J. et al. Disordered methionine metabolism in MTAP/CDKN2A-deleted cancers leads to dependence on PRMT5. Science 351, 1208–1213 (2016).

    CAS  PubMed  Google Scholar 

  115. Kryukov, G. V. et al. MTAP deletion confers enhanced dependency on the PRMT5 arginine methyltransferase in cancer cells. Science 351, 1214–1218 (2016). References 114 and 115 showed that MTAP deletion leads to PRMT5 dependence.

    CAS  PubMed  PubMed Central  Google Scholar 

  116. Schmid, M. et al. Homozygous deletions of methylthioadenosine phosphorylase (MTAP) are more frequent than p16INK4A (CDKN2) homozygous deletions in primary non-small cell lung cancers (NSCLC). Oncogene 17, 2669–2675 (1998).

    CAS  PubMed  Google Scholar 

  117. Illei, P. B., Rusch, V. W., Zakowski, M. F. & Ladanyi, M. Homozygous deletion of CDKN2A and codeletion of the methylthioadenosine phosphorylase gene in the majority of pleural mesotheliomas. Clin. Cancer Res. 9, 2108–2113 (2003).

    CAS  PubMed  Google Scholar 

  118. Kindler, H. L., Burris, H. A. III, Sandler, A. B. & Oliff, I. A. A phase II multicenter study of L-alanosine, a potent inhibitor of adenine biosynthesis, in patients with MTAP-deficient cancer. Invest. New Drugs 27, 75–81 (2009).

    CAS  PubMed  Google Scholar 

  119. Delage, B. et al. Arginine deprivation and argininosuccinate synthetase expression in the treatment of cancer. Int. J. Cancer 126, 2762–2772 (2010).

    CAS  PubMed  Google Scholar 

  120. Szlosarek, P. W. et al. In vivo loss of expression of argininosuccinate synthetase in malignant pleural mesothelioma is a biomarker for susceptibility to arginine depletion. Clin. Cancer Res. 12, 7126–7131 (2006).

    CAS  PubMed  Google Scholar 

  121. Szlosarek, P. W. et al. Arginine deprivation with pegylated arginine deiminase in patients with argininosuccinate synthetase 1-deficient malignant pleural mesothelioma: a randomized clinical trial. JAMA Oncol. 3, 58–66 (2017). Proof-of-concept study demonstrating the role of arginine deprivation in ASS1 -deficient mesothelioma.

    PubMed  Google Scholar 

  122. Beddowes, E. et al. Phase 1 dose-escalation study of pegylated arginine deiminase, cisplatin, and pemetrexed in patients with argininosuccinate synthetase 1-deficient thoracic cancers. J. Clin. Oncol. 35, 1778–1785 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  123. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02709512 (2017).

  124. Mossman, B. T. et al. New insights into understanding the mechanisms, pathogenesis, and management of malignant mesotheliomas. Am. J. Pathol. 182, 1065–1077 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  125. Bograd, A. J. et al. Immune responses and immunotherapeutic interventions in malignant pleural mesothelioma. Cancer Immunol. Immunother. 60, 1509–1527 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  126. Cornelissen, R. et al. Ratio of intratumoral macrophage phenotypes is a prognostic factor in epithelioid malignant pleural mesothelioma. PLoS ONE 9, e106742 (2014).

    PubMed  PubMed Central  Google Scholar 

  127. Ujiie, H. et al. The tumoral and stromal immune microenvironment in malignant pleural mesothelioma: a comprehensive analysis reveals prognostic immune markers. Oncoimmunology 4, e1009285 (2015).

    PubMed  PubMed Central  Google Scholar 

  128. Coussens, L. M., Zitvogel, L. & Palucka, A. K. Neutralizing tumor-promoting chronic inflammation: a magic bullet? Science 339, 286–291 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  129. Lievense, L. A. et al. Precision immunotherapy; dynamics in the cellular profile of pleural effusions in malignant mesothelioma patients. Lung Cancer 107, 36–40 (2017).

    PubMed  Google Scholar 

  130. Dostert, C. et al. Innate immune activation through Nalp3 inflammasome sensing of asbestos and silica. Science 320, 674–677 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  131. Sekido, Y. Molecular pathogenesis of malignant mesothelioma. Carcinogenesis 34, 1413–1419 (2013).

    CAS  PubMed  Google Scholar 

  132. Balkwill, F., Charles, K. A. & Mantovani, A. Smoldering and polarized inflammation in the initiation and promotion of malignant disease. Cancer Cell 7, 211–217 (2005).

    CAS  PubMed  Google Scholar 

  133. Lo, A. et al. Tumor-promoting desmoplasia is disrupted by depleting FAP-expressing stromal cells. Cancer Res. 75, 2800–2810 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  134. Wang, L. C. et al. Targeting fibroblast activation protein in tumor stroma with chimeric antigen receptor T cells can inhibit tumor growth and augment host immunity without severe toxicity. Cancer Immunol. Res. 2, 154–166 (2014).

    CAS  PubMed  Google Scholar 

  135. Meerang, M. et al. Antagonizing the Hedgehog pathway with vismodegib impairs malignant pleural mesothelioma growth in vivo by affecting stroma. Mol. Cancer Ther. 15, 1095–1105 (2016).

    CAS  PubMed  Google Scholar 

  136. Lievense, L. A., Bezemer, K., Aerts, J. G. & Hegmans, J. P. Tumor-associated macrophages in thoracic malignancies. Lung Cancer 80, 256–262 (2013).

    CAS  PubMed  Google Scholar 

  137. Holzel, M., Bovier, A. & Tuting, T. Plasticity of tumour and immune cells: a source of heterogeneity and a cause for therapy resistance? Nat. Rev. Cancer 13, 365–376 (2013).

    PubMed  Google Scholar 

  138. Lievense, L. A. et al. Pleural effusion of patients with malignant mesothelioma induces macrophage-mediated T cell suppression. J. Thorac. Oncol. 11, 1755–1764 (2016).

    PubMed  Google Scholar 

  139. Awad, M. M. et al. Cytotoxic T cells in PD-L1-positive malignant pleural mesotheliomas are counterbalanced by distinct immunosuppressive factors. Cancer Immunol. Res. 4, 1038–1048 (2016).

    CAS  PubMed  Google Scholar 

  140. van der Most, R. G. et al. Tumor eradication after cyclophosphamide depends on concurrent depletion of regulatory T cells: a role for cycling TNFR2-expressing effector-suppressor T cells in limiting effective chemotherapy. Cancer Immunol. Immunother. 58, 1219–1228 (2009).

    CAS  PubMed  Google Scholar 

  141. Veltman, J. D. et al. COX-2 inhibition improves immunotherapy and is associated with decreased numbers of myeloid-derived suppressor cells in mesothelioma. Celecoxib influences MDSC function. BMC Cancer 10, 464 (2010).

    PubMed  PubMed Central  Google Scholar 

  142. Veltman, J. D. et al. Zoledronic acid impairs myeloid differentiation to tumour-associated macrophages in mesothelioma. Br. J. Cancer 103, 629–641 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  143. Veltman, J. D. et al. Low-dose cyclophosphamide synergizes with dendritic cell-based immunotherapy in antitumor activity. J. Biomed. Biotechnol. 2010, 798467 (2010).

    PubMed  PubMed Central  Google Scholar 

  144. Ellis, L. M. & Hicklin, D. J. VEGF-targeted therapy: mechanisms of anti-tumour activity. Nat. Rev. Cancer 8, 579–591 (2008).

    CAS  PubMed  Google Scholar 

  145. Strizzi, L. et al. Vascular endothelial growth factor is an autocrine growth factor in human malignant mesothelioma. J. Pathol. 193, 468–475 (2001).

    CAS  PubMed  Google Scholar 

  146. Linder, C., Linder, S., Munck-Wikland, E. & Strander, H. Independent expression of serum vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) in patients with carcinoma and sarcoma. Anticancer Res. 18, 2063–2068 (1998).

    CAS  PubMed  Google Scholar 

  147. Hilberg, F. et al. BIBF 1120: triple angiokinase inhibitor with sustained receptor blockade and good antitumor efficacy. Cancer Res. 68, 4774–4782 (2008).

    CAS  PubMed  Google Scholar 

  148. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT01907100 (2017).

  149. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02863055 (2016).

  150. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02555007 (2015).

  151. Kerbel, R. S. & Kamen, B. A. The anti-angiogenic basis of metronomic chemotherapy. Nat. Rev. Cancer 4, 423–436 (2004).

    CAS  PubMed  Google Scholar 

  152. Lievense, L. A., Sterman, D. H., Cornelissen, R. & Aerts, J. G. Checkpoint blockade in lung cancer and mesothelioma. Am. J. Respir. Crit. Care Med. https://doi.org/10.1164/rccm.201608-1755CI (2017).

  153. Combaz-Lair, C. et al. Immune biomarkers PD-1/PD-L1 and TLR3 in malignant pleural mesotheliomas. Hum. Pathol. 52, 9–18 (2016).

    CAS  PubMed  Google Scholar 

  154. Kindler, H. L. et al. Tremelimumab as second- or third-line treatment of unresectable malignant mesothelioma (MM): results from the global, double-blind, placebo-controlled DETERMINE study [abstract]. J. Clin. Oncol. 34 (Suppl.) 8502 (2016).

    Google Scholar 

  155. Calabro, L. et al. Tremelimumab for patients with chemotherapy-resistant advanced malignant mesothelioma: an open-label, single-arm, phase 2 trial. Lancet Oncol. 14, 1104–1111 (2013). Phase II trial of tremelimumab for patients with chemotherapy-resistant advanced malignant mesothelioma.

    CAS  PubMed  Google Scholar 

  156. Guazzelli, A. et al. Anti-CTLA-4 therapy for malignant mesothelioma. Immunotherapy 9, 273–280 (2017).

    CAS  PubMed  Google Scholar 

  157. Alley, E. W. et al. Clinical safety and activity of pembrolizumab in patients with malignant pleural mesothelioma (KEYNOTE-028): preliminary results from a non-randomised, open-label, phase 1b trial. Lancet Oncol. 18, 623–630 (2017). Phase Ib trial of pembrolizumab in patients with malignant pleural mesothelioma.

    CAS  PubMed  Google Scholar 

  158. Quispel-Janssen, J. et al. A phase II study of ivolumab in malignant pleural mesothelioma (NivoMes): with translational research (TR) biopies [OA13.01]. J. Thorac. Oncol. 12, S292–S293 (2017).

    Google Scholar 

  159. US National Library of Medicine. ClinicalTrials.gov https://www.clinicaltrials.gov/ct2/show/NCT03063450 (2017).

  160. Hassan, R. et al. Avelumab (MSB0010718C; anti-PD-L1) in patients with advanced unresectable mesothelioma from the JAVELIN solid tumor phase Ib trial: safety, clinical activity, and PD-L1 expression [abstract]. J. Clin. Oncol. 34 (Suppl.), 8503 (2016).

    Google Scholar 

  161. US National Library of Medicine. ClinicalTrials.gov https://www.clinicaltrials.gov/ct2/show/NCT02588131 (2015).

  162. US National Library of Medicine. ClinicalTrials.gov https://www.clinicaltrials.gov/ct2/show/NCT02716272 (2016).

  163. US National Library of Medicine. ClinicalTrials.gov https://www.clinicaltrials.gov/ct2/show/NCT02899299 (2017).

  164. Marcq, E., Pauwels, P., van Meerbeeck, J. P. & Smits, E. L. Targeting immune checkpoints: new opportunity for mesothelioma treatment? Cancer Treat. Rev. 41, 914–924 (2015).

    CAS  PubMed  Google Scholar 

  165. Serrels, A. et al. Nuclear FAK controls chemokine transcription, Tregs, and evasion of anti-tumor immunity. Cell 163, 160–173 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  166. US National Library of Medicine. ClinicalTrials.gov https://www.clinicaltrials.gov/ct2/show/NCT02758587 (2017).

  167. Aerts, J. G., Lievense, L. A., Hoogsteden, H. C. & Hegmans, J. P. Immunotherapy prospects in the treatment of lung cancer and mesothelioma. Transl Lung Cancer Res. 3, 34–45 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  168. Dammeijer, F. et al. Efficacy of tumor vaccines and cellular immunotherapies in non-small-cell lung cancer: a systematic review and meta-analysis. J. Clin. Oncol. 34, 3204–3212 (2016).

    CAS  PubMed  Google Scholar 

  169. Cornelissen, R. et al. Extended tumor control after dendritic cell vaccination with low-dose cyclophosphamide as adjuvant treatment in patients with malignant pleural mesothelioma. Am. J. Respir. Crit. Care Med. 193, 1023–1031 (2016).

    CAS  PubMed  Google Scholar 

  170. Hegmans, J. P. et al. Consolidative dendritic cell-based immunotherapy elicits cytotoxicity against malignant mesothelioma. Am. J. Respir. Crit. Care Med. 181, 1383–1390 (2010).

    CAS  PubMed  Google Scholar 

  171. Aerts, J. et al. Autologous dendritic cells loaded with allogeneic tumor cell lysate (Pheralys®) in patients with mesothelioma: final results of a phase I study [abstract OA13.06]. J. Thorac. Oncol. 12 (Suppl.), S295 (2017).

    Google Scholar 

  172. Sterman, D. H. et al. Pilot and feasibility trial evaluating immuno-gene therapy of malignant mesothelioma using intrapleural delivery of adenovirus-IFNalpha combined with chemotherapy. Clin. Cancer Res. 22, 3791–3800 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  173. Sterman, D. H. et al. A trial of intrapleural adenoviral-mediated Interferon-alpha2b gene transfer for malignant pleural mesothelioma. Am. J. Respir. Crit. Care Med. 184, 1395–1399 (2011).

    PubMed  PubMed Central  Google Scholar 

  174. Morello, A., Sadelain, M. & Adusumilli, P. S. Mesothelin-targeted CARs: driving T cells to solid tumors. Cancer Discov. 6, 133–146 (2016). Interesting article on using CAR T cells in solid tumours, including mesothelioma.

    CAS  PubMed  Google Scholar 

  175. Beatty, G. L. et al. Mesothelin-specific chimeric antigen receptor mRNA-engineered T cells induce anti-tumor activity in solid malignancies. Cancer Immunol. Res. 2, 112–120 (2014).

    CAS  PubMed  Google Scholar 

  176. Antonia, S. J., Vansteenkiste, J. F. & Moon, E. Immunotherapy: beyond anti-PD-1 and anti-PD-L1 therapies. Am. Soc. Clin. Oncol. Educ. Book 35, e450–e458 (2016).

    PubMed  Google Scholar 

  177. Galateau-Salle, F., Churg, A., Roggli, V., Travis, W. D. & World Health Organization Committee for Tumors of the Pleura. The 2015 World Health Organization Classification of Tumors of the Pleura: advances since the 2004 Classification. J. Thorac. Oncol. 11, 142–154 (2016).

    PubMed  Google Scholar 

  178. International Agency for Research on Cancer. A Review of Human Carcinogens: Arsenic, Metals, Fibres, and Dusts (WHO Press, 2012).

  179. Bianchi, C. & Bianchi, T. Global mesothelioma epidemic: trend and features. Indian J. Occup. Environ. Med. 18, 82–88 (2014).

    PubMed  PubMed Central  Google Scholar 

  180. Joshi, T. K., Bhuva, U. B. & Katoch, P. Asbestos ban in India: challenges ahead. Ann. NY Acad. Sci. 1076, 292–308 (2006).

    PubMed  Google Scholar 

  181. World Health Organization. Chrysotile asbestos. WHO http://apps.who.int/iris/bitstream/10665/143649/1/9789241564816_eng.pdf?ua=1 (2014).

  182. Baumann, F., Ambrosi, J. P. & Carbone, M. Asbestos is not just asbestos: an unrecognised health hazard. Lancet Oncol. 14, 576–578 (2013). Important article on asbestos as a health hazard.

    PubMed  Google Scholar 

  183. Artvinli, M. & Baris, Y. I. Malignant mesotheliomas in a small village in the Anatolian region of Turkey: an epidemiologic study. J. Natl Cancer Inst. 63, 17–22 (1979).

    CAS  PubMed  Google Scholar 

  184. Comba, P., Gianfagna, A. & Paoletti, L. Pleural mesothelioma cases in Biancavilla are related to a new fluoro-edenite fibrous amphibole. Arch. Environ. Health 58, 229–232 (2003).

    PubMed  Google Scholar 

  185. Ministry of Labour and Factory Inspectorate. Annual Report for 1947 79–80 (HMSO, 1949).

  186. Doll, R. Mortality from lung cancer in asbestos workers. Br. J. Ind. Med. 12, 81–86 (1955).

    CAS  PubMed  PubMed Central  Google Scholar 

  187. Selikoff, I. J., Churg, J. & Hammond, E. C. Asbestos exposure and neoplasia. JAMA 188, 22–26 (1964).

    CAS  PubMed  Google Scholar 

  188. Newhouse, M. L. & Thompson, H. Mesothelioma of pleura and peritoneum following exposure to asbestos in the London area. Br. J. Ind. Med. 22, 261–269 (1965).

    CAS  PubMed  PubMed Central  Google Scholar 

  189. The Asbestos Regulations 1969, No. 690, UK Statutory Instrument.

  190. United States Clean Air Act, 42 U.S.C. section 7401 et seq. (1970).

  191. United States Toxic Substances Control Act, 15 U.S.C. section 2601 et seq. (1976).

  192. International Agency for Research on Cancer. IARC Monographs on the Evaluation of Carcinogenic Risks of Chemicals to Man: volume 14, Asbestos (IARC, 1977).

  193. The Asbestos (Prohibitions) Regulations 1985, No. 910, UK Statutory Instrument.

  194. The Control of Asbestos at Work Regulations 1987, No. 2115, UK Statutory Instrument.

  195. International Agency for Research on Cancer. Overall Evaluations of Carcinogenicity: an Updating of IARC Monographs 1–42 106–116 (IARC, 1987).

  196. Dogan, A. U. et al. Genetic predisposition to fiber carcinogenesis causes a mesothelioma epidemic in Turkey. Cancer Res. 66, 5063–5068 (2006).

    CAS  PubMed  Google Scholar 

  197. The Control of Asbestos Regulations 2006, No. 2739, UK Statutory Instrument.

  198. Napolitano, A. et al. Minimal asbestos exposure in germline BAP1 heterozygous mice is associated with deregulated inflammatory response and increased risk of mesothelioma. Oncogene 35, 1996–2002 (2016).

    CAS  PubMed  Google Scholar 

  199. Harvey, K. F., Zhang, X. & Thomas, D. M. The Hippo pathway and human cancer. Nat. Rev. Cancer 13, 246–257 (2013).

    CAS  PubMed  Google Scholar 

  200. Carbone, M. & Yang, H. Molecular pathways: targeting mechanisms of asbestos and erionite carcinogenesis in mesothelioma. Clin. Cancer Res. 18, 598–604 (2012).

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

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

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Timothy A. Yap.

Ethics declarations

Competing interests

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.

Supplementary information

Supplementary information S1 (table)

Ongoing clinical trials in mesothelioma (PDF 149 kb)

PowerPoint slides

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.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

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

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrc.2017.42

This article is cited by

Search

Quick links

Nature Briefing: Cancer

Sign up for the Nature Briefing: Cancer newsletter — what matters in cancer research, free to your inbox weekly.

Get what matters in cancer research, free to your inbox weekly. Sign up for Nature Briefing: Cancer