Malignant pleural mesothelioma as an epigenetic disease

Written by Dr Anne-Marie Baird, Queensland University of Technology, Australia

Malignant pleural mesothelioma (MPM) arises in the pleural cavity in the lungs, from the mesothelial cells. It is an aggressive inflammatory cancer, which has been associated with asbestos exposure since the early 1960s. The lag period between exposure and the development of MPM is significant, anywhere between 20-40 years. Conservative estimates have determined that 43,000 people die from this disease each year.

A number of epigenetic events are observed in MPM. DNMT1/DNMT3A/DNMT3B are all overexpressed in MPM and may contribute to carcinogenesis as targeting these with antisense oligos result in MPM growth inhibition.1Some studies have shown specific methylation profiles in MPM compared with normal pleura samples.2Genes that are significantly changed through methylation are ESR1, SLC6A20, and SYK.3 In addition, WIF-1, SFR (1, 2, 4) promoter methylation was observed in a high number of mesothelioma tissue samples.4MPM patients with methylation of TMS1 or HIC-1had significantly reduced overall survival.5

Furthermore, in a large cohort of MPM patient samples there was a high incidence of hypermethylation at the promoter region of E-cadherin and FHIT and to a lesser extent at p16, APC1B, p14, RARβ, APC1A, RASSF1A and DAPK.6 Patients with methylation of RARβ with either DAPK or RASSF1A had a shorter overall survival compared with patients who had only one or no epigenetic alteration.6

Epigenetic facilitators of stem cell pluripotency are the PcG group of proteins with EZH2 and EED being part of the PRC-2. EZH2 was overexpressed in MPM patient samples compared with normal pleura.7 This increase was associated with decreased survival. Knockdown of these genes or treatment with DZnep resulted in decreased H3K27Me3 levels.8 Functionally there was a significant inhibition in cellular proliferation and migration of MPM cells. DZNep treatment reduced tumour size by 50% and decreased H3K27Me3 levels within the RASSF1A, HIC-1 and p21 promoters. H3K27Me3 levels within the promoters of RASSFIA and HIC-1 were markedly decreased in cells exhibiting knockdown of EZH2 or EED.7

Asbestos can also alter the epigenome with methylation of p16, CDKN2B and RASSF1 significantly associated with asbestos exposure.2 The methylation of MT1A was also correlated with asbestos burden.2, 3 Increased asbestos burden was associated with increased hypermethylation of cell cycle genes such as APC, CCND2 in addition to those mentioned above.9

LungsEpigenetic therapy for MPM

The current standard of care for MPM patients is pemetrexed and cisplatin. One study has shown that HDi, VPA, in combination with these drugs improved apoptosis in MPM cell lines and in cells from patient biopsies. In a mouse model of MPM, a combination of all three drugs resulted in tumour growth inhibition.10 In a phase II trial of VPA with doxorubicin, resulted in 7 partial responses in MPM patients.11In a Phase I Study of SAHA in advanced cancer (13 MPM cases), resulted in two partial responses with increased acetylation in PBMCs.12 In a Phase II study, PDX101 (Bellinostat) was not effective as a mono-therapy with no objective responses.13 In MPM animal models, panobinostat treatment significantly reduced tumour growth compared with untreated mice.14One of the biggest mesothelioma trials to date was VANTAGE 14. This was a Phase III study using vorinostat or placebo in a cohort of 661 patients who had previously been treated with chemotherapy. Vorinostat did not improve survival compared with placebo, with median survivals of 31 weeks and 27 weeks, respectively. However, progression free survival was improved but not in a clinically relevant way (Source: European Multidisciplinary Cancer Congress).

In MPM cell lines, DAC induced senescence possibly through an increase in β galactosidase and also increased the phosphorylation γH2AX.15 In addition, DAC treatment reduced MPM cell survival through an up-regulation of p21 levels.16DAC in combination with VPA demonstrated synergistic effects in reducing MPM cellular survival and induced tumour antigen expression, thus increasing cell killing through CD8+ cytotoxic T cells. This combination in vivo inhibited tumour growth and potentiated the immune response.17 DAC can stimulate the expression of a range of antigens in MPM cell lines such as MAGE-1, -2, -3 and -4, NY-ESO-1 and SSX-2.18 In a phase I trial (6 MPM cases), DAC resulted in no responses in MPM patients, however there was a re-expression of NY-ESO-1, MAGE3 and p16.19

Given the dysfunctional epigenetic background of MPM and the influence of asbestos on the epigenetic regulation of a number of critical genes, it is possible that combinations of HDi or DNMTi in conjunction with chemotherapy or other targeted agents may provide much needed therapeutic benefit for MPM patients.

 

References:

  1. Kassis ES, Zhao M, Hong JA, Chen GA, Nguyen DM, Schrump DS. Depletion of DNA methyltransferase 1 and/or DNA methyltransferase 3b mediates growth arrest and apoptosis in lung and esophageal cancer and malignant pleural mesothelioma cells. The Journal of thoracic and cardiovascular surgery 2006; 131(2): 298-306.
  2. Christensen BC, Houseman EA, Godleski JJ, et al. Epigenetic profiles distinguish pleural mesothelioma from normal pleura and predict lung asbestos burden and clinical outcome. Cancer research 2009; 69(1): 227-34.
  3. Tsou JA, Galler JS, Wali A, et al. DNA methylation profile of 28 potential marker loci in malignant mesothelioma. Lung cancer (Amsterdam, Netherlands) 2007; 58(2): 220-30.
  4. Kohno H, Amatya VJ, Takeshima Y, et al. Aberrant promoter methylation of WIF-1 and SFRP1, 2, 4 genes in mesothelioma. Oncology reports 2010; 24(2): 423-31.
  5. Suzuki M, Toyooka S, Shivapurkar N, et al. Aberrant methylation profile of human malignant mesotheliomas and its relationship to SV40 infection. Oncogene 2005; 24(7): 1302-8.
  6. Fischer JR, Ohnmacht U, Rieger N, et al. Promoter methylation of RASSF1A, RARbeta and DAPK predict poor prognosis of patients with malignant mesothelioma. Lung cancer (Amsterdam, Netherlands) 2006; 54(1): 109-16.
  7. Kemp CD, Rao M, Xi S, et al. Polycomb repressor complex-2 is a novel target for mesothelioma therapy. Clinical cancer research : an official journal of the American Association for Cancer Research 2012; 18(1): 77-90.
  8. Tessema M, Yingling CM, Thomas CL, et al. SULF2 methylation is prognostic for lung cancer survival and increases sensitivity to topoisomerase-I inhibitors via induction of ISG15. Oncogene 2012; 31(37): 4107-16.
  9. Christensen BC, Godleski JJ, Marsit CJ, et al. Asbestos exposure predicts cell cycle control gene promoter methylation in pleural mesothelioma. Carcinogenesis 2008; 29(8): 1555-9.
  10. Vandermeers F, Hubert P, Delvenne P, et al. Valproate, in combination with pemetrexed and cisplatin, provides additional efficacy to the treatment of malignant mesothelioma. Clinical cancer research : an official journal of the American Association for Cancer Research 2009; 15(8): 2818-28.
  11. Scherpereel A, Berghmans T, Lafitte JJ, et al. Valproate-doxorubicin: promising therapy for progressing mesothelioma. A phase II study. The European respiratory journal 2011; 37(1): 129-35.
  12. Krug LM, Curley T, Schwartz L, et al. Potential role of histone deacetylase inhibitors in mesothelioma: clinical experience with suberoylanilide hydroxamic acid. Clinical lung cancer 2006; 7(4): 257-61.
  13. Ramalingam SS, Belani CP, Ruel C, et al. Phase II study of belinostat (PXD101), a histone deacetylase inhibitor, for second line therapy of advanced malignant pleural mesothelioma. Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer 2009; 4(1): 97-101.
  14. Crisanti MC, Wallace AF, Kapoor V, et al. The HDAC inhibitor panobinostat (LBH589) inhibits mesothelioma and lung cancer cells in vitro and in vivo with particular efficacy for small cell lung cancer. Molecular cancer therapeutics 2009; 8(8): 2221-31.
  15. Amatori S, Bagaloni I, Viti D, Fanelli M. Premature senescence induced by DNA demethylating agent (Decitabine) as therapeutic option for malignant pleural mesothelioma. Lung cancer (Amsterdam, Netherlands) 2011; 71(1): 113-5.
  16. Amatori S, Papalini F, Lazzarini R, et al. Decitabine, differently from DNMT1 silencing, exerts its antiproliferative activity through p21 upregulation in malignant pleural mesothelioma (MPM) cells. Lung cancer (Amsterdam, Netherlands) 2009; 66(2): 184-90.
  17. Leclercq S, Gueugnon F, Boutin B, et al. A 5-aza-2′-deoxycytidine/valproate combination induces cytotoxic T-cell response against mesothelioma. The European respiratory journal 2011; 38(5): 1105-16.
  18. Sigalotti L, Coral S, Altomonte M, et al. Cancer testis antigens expression in mesothelioma: role of DNA methylation and bioimmunotherapeutic implications. British journal of cancer 2002; 86(6): 979-82.
  19. Schrump DS, Fischette MR, Nguyen DM, et al. Phase I study of decitabine-mediated gene expression in patients with cancers involving the lungs, esophagus, or pleura. Clinical cancer research : an official journal of the American Association for Cancer Research 2006; 12(19): 5777-85.

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