First-in-human trial of a STAT3 decoy oligonucleotide in head and neck tumors: implications for cancer therapy.
First-in-human trial of a STAT3 decoy oligonucleotide in head and neck tumors: implications for cancer therapy.
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DOI：
10.1158/2159-8290.cd-12-0191
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发表时间：
2012-08
期刊：
影响因子：
28.2
通讯作者：
Grandis JR
中科院分区：
文献类型：
--
作者：
Sen M;Thomas SM;Kim S;Yeh JI;Ferris RL;Johnson JT;Duvvuri U;Lee J;Sahu N;Joyce S;Freilino ML;Shi H;Li C;Ly D;Rapireddy S;Etter JP;Li PK;Wang L;Chiosea S;Seethala RR;Gooding WE;Chen X;Kaminski N;Pandit K;Johnson DE;Grandis JR
尽管有证据表明包括 STAT3 在内的转录因子与肿瘤发生有关，但这些蛋白质仍被认为是“不可成药的”。我们开发了一种针对 STAT3 的诱饵并进行了 0 期试验。与接受盐水对照的肿瘤相比，注射 STAT3 诱饵后，头颈癌中 STAT3 靶基因的表达水平降低。由于不稳定，诱饵不适合全身给药。为了克服这一障碍，我们使用六乙二醇间隔基连接寡核苷酸链。这种环状 STAT3 诱饵以高亲和力与 STAT3 蛋白结合，降低细胞活力，并抑制癌细胞中 STAT3 靶基因的表达。静脉注射环状 STAT3 诱饵可抑制异种移植物生长并下调肿瘤中的 STAT3 靶基因。这些结果首次证明了通过全身施用选择性 STAT3 抑制剂来抑制肿瘤 STAT3 信号传导的成功策略，从而为广泛的临床开发铺平了道路。
Despite evidence implicating transcription factors, including STAT3, in oncogenesis, these proteins have been regarded as “undruggable”. We developed a decoy targeting STAT3 and performed a phase 0 trial. Expression levels of STAT3 target genes were decreased in the head and neck cancers following injection with the STAT3 decoy compared with tumors receiving saline control. Decoys have not been amenable to systemic administration due to instability. To overcome this barrier, we linked the oligonucleotide strands using hexa-ethyleneglycol spacers. This cyclic STAT3 decoy bound with high affinity to STAT3 protein, reduced cellular viability, and suppressed STAT3 target gene expression in cancer cells. Intravenous injection of the cyclic STAT3 decoy inhibited xenograft growth and downregulated STAT3 target genes in the tumors. These results provide the first demonstration of a successful strategy to inhibit tumor STAT3 signaling via systemic administration of a selective STAT3 inhibitor, thereby paving the way for broad clinical development.