**7. Epigenetics in the treatment of mesothelioma**

MPM inhibits tumor suppressor genes by promoting LOI and repression of CG genes by site-specific hypermethylation of DNA and/or polycomb repressor complexes in the context of hypomethylation of the genome. This "DNA methylation paradox" mimics epigenomic conditions in normal germ cells and lays the groundwork for epigenetic regimens that restore tumor suppressor gene expression and trigger growth arrest/apoptosis. Upregulation of CTAs, development of viral mimicry by derepression of endogenous retroviruses, and control of the tumor microenvironment all help to boost antitumor immunity [89, 90].

DNMTs are potential targets for MPM treatment because of their direct functions in suppressing tumor suppressor genes and maintaining pluripotency [91, 92]. Previous clinical attempts to inhibit DNMT activity in MPM, however, have failed miserably. Yogelzang et al. [93] showed a 17% objective response rate in 41 MPM patients who received 120 h of continuous dihydro-5-azacytidine infusions. Amazingly, 6 years following treatment, the single responder was diseasefree. The lack of efficacy of DNA hypomethylating drugs in solid tumors could be due to their usage at maximum tolerated doses, resulting in myelosuppression, rather than prolonged use at lower doses to obtain pharmacodynamic effects without systemic toxicity. The Phase I decitabine trial (DAC) clearly demonstrates that chronic exposures are required to achieve maximum gene induction effects in cancer tissues [94].

Furthermore, 5-AZA and DAC administered IV, SQ, or PO have short half-lives (less than 5 min) and poor biodistribution, limiting their potential utility in patients with solid tumors. Cytidine deaminase (CDA), which is found in practically all organs but mainly the gastrointestinal system, quickly inactivates these molecules [95, 96]. Documented toxicity increases Cmax and t1/2 (>50 nM and 4 h, respectively) as well as biodistribution of oral decitabine, decreasing inter-patient variability in drug levels significantly [95–98]. Significant increases in fetal hemoglobin, without neutropenia, thrombocytopenia, or lymphopenia, are indicative of hypomethylation of systemic DNA caused by oral DAC-THU. A phase II trial (NCT02664181) is currently underway at the Cleveland Clinic and NCI to examine whether DAC/THU can improve responses to nivolumab when given as second-line therapy to patients with non-small cell lung cancer. Despite encouraging preclinical data [26], efforts to target HDAC on MPM have also been disappointing.

As second- or third-line therapy, Krug et al. [99] randomized 661 MPM patients to receive the HDAC inhibitor vorinostat or placebo. Overall survival, as well as the drug's safety and tolerability, were the key outcomes. Vorinostat-treated patients had a median OS of 30.7 weeks (95% CI 26.7–36.1) compared to 27 weeks (95% CI 23.1– 31.9) for placebo-treated patients. Given the absence of evidence for HDAC upregulation in MPM and the limited antitumor effects of HDAC inhibitors alone in preclinical tests, the lack of efficacy of the single-agent vorinostat in patients with MPM is not surprising. Combinated techniques, such as using HDAC inhibitors to sensitize cells to TRAIL-mediated apoptosis or flavopiridol to boost romidepsin-mediated growth arrest and death, might be helpful for future clinical trials. Hypomethylating drugs, on the other hand, do not appear to lessen the incidence of mesothelioma after asbestos exposure. In fact, non-solid cancers such leukemias, lymphomas, and other myelodysplastic syndromes show the best benefits with this medicine.

It is feasible that BAP1 mutations could be used for MPM therapy in the future. BAP1 promotes the recruitment of the polychial deubiquitinase PR-DUB complex to *Epigenomics in Malignant Pleural Mesothelioma DOI: http://dx.doi.org/10.5772/intechopen.105408*

DNA damage sites by stabilizing BRCA-1 and promoting poly (ADP-Ribose) dependent recruitment of the polychial deubiquitinase PR-DUB complex to DNA damage sites. This activity is dependent on deubiquitinase activity and BAP1 phosphorylation. BAP1 mutations, which invariably show as a loss of function, cause BRCA-1 levels to drop and double-stranded DNA repair to be inhibited [100–102]. A BAP1 isoform including part of the catalytic domain sensitized MPM cells to the PARP1 inhibitor, according to Parotta et al. [102]. (Olaparib). Concomitant treatment with GDC0980, a dual PI3K-mTOR inhibitor that is downregulated by BRCA-1, could improve this sensitivity. These strategies could improve responses to cisplatin/pemetrexed in patients with BAP1 mutant MPM and should be evaluated in future clinical trials.

There is considerable interest in chromatographic remodeling agents with adoptive cell transfer or immune checkpoint inhibitors for cancer therapy, given the extensive preclinical studies showing DNA demethylating agents, HDAC inhibitors, and KMT inhibitors in the immunomodulatory effects of potentials [103]. In a syngeneic mouse tumor model, cytolytic T lymphocytes target testicular cancer antigen in vivo using decitabine to destroy metastatic cancer. The preclinical basis for combining gene induction regimens with cancer adoptive immunotherapy was established in these studies. Furthermore, novel microenvironmental data are likely to have a substantial impact on the outcomes of clinical trials for epigenetic treatments and immunotherapies [89].
