Malignant pleural mesothelioma as an epigenetic disease

萨姆罗斯

由Anne-Marie Baird博士撰写，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.

在MPM中观察到许多表观遗传事件。DNMT1 / DNMT3A / DNMT3A全部在MPM中过表达，可以有助于致癌，因为用反义寡核苷酸导致MPM生长抑制产生。1与正常胸膜样品相比，一些研究表明了MPM中的特定甲基化谱。2Genes that are significantly changed through methylation are ESR1, SLC6A20, and SYK.3.此外,WIF-1 SFR(1、2、4)启动子methylation was observed in a high number of mesothelioma tissue samples.4.MPM 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.与只有一个或没有表观遗传改变的患者相比，患有DAPK或RASSF1A的RARβ甲基化的患者较短。6.

表观遗传的主持人干细胞多能性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.

石棉还可以改变与石棉暴露显着相关的P16，CDKN2B和RASSF1的外延蛋白酶。2MT1a的甲基化也与石棉负担相关。2那3.由于上述那些，增加了石棉负担的增加与细胞周期基因如APC，CCND2的高甲基化。9.

LungsMPM的表观遗传疗法

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.在具有多柔比星的VPA的II期试验中，导致MPM患者的7个部分反应。11.In 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.在MPM动物模型中，与未处理的小鼠相比，Panobinostat治疗显着降低了肿瘤生长。14.One 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.此外，DAC治疗通过P21水平的上调降低MPM细胞存活。16.DAC 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体内inhibited tumour growth and potentiated the immune response.17.DAC可以刺激MPM细胞系中一系列抗原的表达，例如MAGE-1，-2，-3和-4，NY-ESO-1和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.

鉴于MPM的功能失调的表观遗传背景和石棉对许多关键基因的表观遗传调节的影响，可以将HDI或DNMTI结合化疗或其他靶向剂的组合可以为MPM患者提供许多所需的治疗益处。

参考：

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