Combination therapy with vidaza and entinostat suppresses tumor growth and reprograms the epigenome in an orthotopic lung cancer model.
Combination therapy with vidaza and entinostat suppresses tumor growth and reprograms the epigenome in an orthotopic lung cancer model.
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DOI：
10.1158/0008-5472.can-10-3184
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发表时间：
2011-01-15
期刊：
影响因子：
11.2
通讯作者：
March TH
中科院分区：
文献类型：
--
作者：
Belinsky SA;Grimes MJ;Picchi MA;Mitchell HD;Stidley CA;Tesfaigzi Y;Channell MM;Liu Y;Casero RA Jr;Baylin SB;Reed MD;Tellez CS;March TH
实体肿瘤的表观遗传治疗可以受益于体内模型，该模型定义了肿瘤的反应性和耐受性特征，以便于患者选择。在此，我们报道了将组蛋白去乙酰酶抑制剂Eninostat与去甲基化药物Vidaza相结合，通过靶向和消融占据肿瘤块高达75%的多形细胞，深刻地影响了K-ras/P53突变肺腺癌在免疫低下的裸鼠体内原位移植的生长。表观遗传疗法对原位生长的K-ras或EGFR突变肿瘤也有类似的减轻肿瘤负担的作用。促凋亡基因和细胞周期蛋白依赖性激酶抑制因子p21的表达增加。数百个基因去甲基化，突出表现为编码转录因子结合蛋白的多梳调控基因和细胞周期的关键调节基因p16基因的重新表达。在涉及细胞周期、DNA损伤、细胞凋亡和组织重塑的关键调控通路中，可以看到高度显著的基因表达变化。这些发现证明了表观遗传疗法在癌症治疗中的前景，并提供了一种原位肺癌模型，该模型可以评估具有不同遗传和表观遗传学特征的肿瘤的治疗效果和表观基因组的重新编程，以指导这些药物的使用。
Epigenetic therapy for solid tumors could benefit from an in vivo model that defines tumor characteristics of responsiveness and resistance to facilitate patient selection. Here we report that combining the histone deacetylase inhibitor entinostat with the demethylating agent vidaza profoundly affected growth of K-ras/p53 mutant lung adenocarcinomas engrafted orthotopically in immunocompromised nude rats by targeting and ablating pleomorphic cells that occupied up to 75% of the tumor masses. A similar reduction in tumor burden was seen with epigenetic therapy in K-ras or EGFR mutant tumors growing orthotopically. Increased expression of pro-apoptotic genes and the cyclin dependent kinase inhibitor p21 was seen. Hundreds of genes were demethylated highlighted by the re-expression of polycomb-regulated genes coding for transcription factor binding proteins and the p16 gene, a key regulator of the cell cycle. Highly significant gene expression changes were seen in key regulatory pathways involved in cell cycle, DNA damage, apoptosis, and tissue remodeling. These findings demonstrate the promise for epigenetic therapy in cancer management and provide an orthotopic lung cancer model that can assess therapeutic efficacy and reprogramming of the epigenome in tumors harboring different genetic and epigenetic profiles to guide use of these drugs.