表观遗传组学——肿瘤精准治疗的新靶标

Epigenomics: a new target for tumor precision treatment

以肿瘤遗传学为基础的个体化治疗已对肿瘤的临床治疗产生影响,例如用于治疗EGFR基因突变肺腺癌的酪氨酸激酶抑制剂吉非替尼,但只有少部分患者具有这种遗传学改变。表观遗传在各种肿瘤中均发生异常改变,且在一定条件下表观遗传改变可以逆转,因此,以表观遗传学为基础的精准治疗将更具有发展和应用前景。已有研究发现表观遗传改变可作为化疗药的敏感性标志物,如MGMT甲基化是脑胶质瘤对烷化剂敏感的标志物,CHFR甲基化是胃癌对多西他赛耐药的标志物等。表观遗传药物也已用于临床,如DNA甲基转移酶抑制剂decitabine和组蛋白去乙酰化酶抑制剂SAHA已用于肿瘤的治疗。目前,许多针对表观遗传调控关键分子的靶向药物正在进行临床试验。联合应用不同的表观遗传药物或化疗药可能达到更好的效果。

Cancer genome-based targeting therapy has already had an impact on tile cnmcai care oi cancer pat^cntv, such as the use of gefitinib to treat cancers with EGFR mutation. However, only a small fraction of cancer patients have driver mutations. Epigenetic events are more often than abnormal genetic changes. Epigenetic changes are likely to com- pose a major component of the ＂dark matter＂ that has high impact on carcinogenesis. The reversibility of epigenetic changes may provide more opportunities and a promising therapeutic strategy. Epigenetic changes may serve as tumor de- tection, prognosis and chemo-sensitive markers. Methylation of MGMT sensitizes gliomas to alkylating agents and methy- lation of CHFR increases resistance of gastric cancer to taxanes are examples for personalized medicine in epigenetics. DNA methyltransferase inhibitor （e. g. decitabine） and histone deacetylase inhibitor （e. g. SAHA） are approved epige- netic drugs. In addition, targeted epigenetic therapies, such as the specific inhibition of enzymes and proteins by small molecules （ e. g. EPZ-6438 ）, are being developed, some of which are in clinical testing. Combined epigenetic therapy and chemo-therapy may achieve increased efficacy and reduced side effects in cancer therapy.