Refractory testicular germ cell tumors are highly sensitive to the second generation DNA methylation inhibitor guadecitabine.
Refractory testicular germ cell tumors are highly sensitive to the second generation DNA methylation inhibitor guadecitabine.
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DOI：
10.18632/oncotarget.13811
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发表时间：
2017-01-10
期刊：
影响因子：
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通讯作者：
Spinella MJ
中科院分区：
文献类型：
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作者：
Albany C;Hever-Jardine MP;von Herrmann KM;Yim CY;Tam J;Warzecha JM;Shin L;Bock SE;Curran BS;Chaudhry AS;Kim F;Sandusky GE;Taverna P;Freemantle SJ;Christensen BC;Einhorn LH;Spinella MJ
睾丸生殖细胞肿瘤(TGCT)是年轻男性最常见的癌症。相当一部分TGCT患者对顺铂耐药。对于这些患者，没有有效的治疗方法，他们中的许多人死于进行性疾病。胚胎癌(EC)是TGCT的干细胞。在先前的体外研究中，我们发现EC细胞对DNA甲基转移酶抑制剂5-氮杂脱氧胞苷(5-aza)高度敏感。在这里，作为将去甲基化治疗引入TGCT患者临床的第一步，我们评估了临床优化的第二代去甲基化药物吉西他滨(SGI-110)对顺铂难治性睾丸癌动物模型中EC细胞的影响。EC细胞对吉西他滨高度敏感，这种超敏反应依赖于高水平的DNA甲基转移酶3B。Guadecitabine介导的EC细胞转录重编程包括P53靶点的诱导和多能性基因的抑制。作为一种单一的药物，即使在远低于冲击实体瘤所需的剂量下，吉西他滨也完全阻止了顺铂耐药的EC异种移植的进展并诱导其完全消退。在体内，低剂量的吉西他滨也能使难治性EC细胞对顺铂增敏。全基因组分析表明，在体内的抗肿瘤活性与P53的激活和免疫相关途径有关，而吉西他滨的抗肿瘤作用依赖于在TGCT中很少突变的P53基因。这些临床前研究结果表明，单用或联合顺铂治疗难治性TGCT患者是一种很有前途的策略。
Testicular germ cell tumors (TGCTs) are the most common cancers of young males. A substantial portion of TGCT patients are refractory to cisplatin. There are no effective therapies for these patients, many of whom die from progressive disease. Embryonal carcinoma (EC) are the stem cells of TGCTs. In prior in vitro studies we found that EC cells were highly sensitive to the DNA methyltransferase inhibitor, 5-aza deoxycytidine (5-aza). Here, as an initial step in bringing demethylation therapy to the clinic for TGCT patients, we evaluated the effects of the clinically optimized, second generation demethylating agent guadecitabine (SGI-110) on EC cells in an animal model of cisplatin refractory testicular cancer. EC cells were exquisitely sensitive to guadecitabine and the hypersensitivity was dependent on high levels of DNA methyltransferase 3B. Guadecitabine mediated transcriptional reprogramming of EC cells included induction of p53 targets and repression of pluripotency genes. As a single agent, guadecitabine completely abolished progression and induced complete regression of cisplatin resistant EC xenografts even at doses well below those required to impact somatic solid tumors. Low dose guadecitabine also sensitized refractory EC cells to cisplatin in vivo. Genome-wide analysis indicated that in vivo antitumor activity was associated with activation of p53 and immune-related pathways and the antitumor effects of guadecitabine were dependent on p53, a gene rarely mutated in TGCTs. These preclinical findings suggest that guadecitabine alone or in combination with cisplatin is a promising strategy to treat refractory TGCT patients.