当前位置: X-MOL 学术Mol. Cancer Ther. › 论文详情
Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)
HIF2α targeted RNAi therapeutic inhibits clear cell renal cell carcinoma
Molecular Cancer Therapeutics ( IF 5.3 ) Pub Date : 2017-10-27 , DOI: 10.1158/1535-7163.mct-17-0471
So C. Wong 1 , Weijun Cheng 1 , Holly Hamilton 1 , Anthony L. Nicholas 1 , Darren H. Wakefield 1 , Aaron Almeida 1 , Andrei V. Blokhin 1 , Jeffrey Carlson 1 , Zane C. Neal 1 , Vladimir Subbotin 1 , Guofeng Zhang 1 , Julia Hegge 1 , Stephanie Bertin 1 , Vladimir S. Trubetskoy 1 , David B. Rozema 1 , David L. Lewis 1 , Steven B. Kanner 1
Affiliation  

Targeted therapy against VEGF and mTOR pathways has been established as the standard-of-care for metastatic clear cell renal cell carcinoma (ccRCC); however, these treatments frequently fail and most patients become refractory requiring subsequent alternative therapeutic options. Therefore, development of innovative and effective treatments is imperative. About 80%–90% of ccRCC tumors express an inactive mutant form of the von Hippel-Lindau protein (pVHL), an E3 ubiquitin ligase that promotes target protein degradation. Strong genetic and experimental evidence supports the correlate that pVHL functional loss leads to the accumulation of the transcription factor hypoxia-inducible factor 2α (HIF2α) and that an overabundance of HIF2α functions as a tumorigenic driver of ccRCC. In this report, we describe an RNAi therapeutic for HIF2α that utilizes a targeting ligand that selectively binds to integrins αvβ3 and αvβ5 frequently overexpressed in ccRCC. We demonstrate that functional delivery of a HIF2α-specific RNAi trigger resulted in HIF2α gene silencing and subsequent tumor growth inhibition and degeneration in an established orthotopic ccRCC xenograft model. Mol Cancer Ther; 17(1); 140–9. ©2017 AACR.

中文翻译:

HIF2α靶向RNAi疗法抑制透明细胞肾细胞癌

针对 VEGF 和 mTOR 通路的靶向治疗已被确立为转移性透明细胞肾细胞癌 (ccRCC) 的标准治疗;然而,这些治疗经常失败并且大多数患者变得难治,需要随后的替代治疗选择。因此,开发创新有效的治疗方法势在必行。大约 80%–90% 的 ccRCC 肿瘤表达 von Hippel-Lindau 蛋白 (pVHL) 的无活性突变形式,pVHL 是一种 E3 泛素连接酶,可促进靶蛋白降解。强有力的遗传和实验证据支持 pVHL 功能丧失导致转录因子缺氧诱导因子 2α (HIF2α) 的积累以及过量的 HIF2α 作为 ccRCC 的致瘤驱动因素的相关性。在这份报告中,我们描述了一种用于 HIF2α 的 RNAi 治疗剂,它利用靶向配体选择性地结合在 ccRCC 中经常过度表达的整联蛋白 αvβ3 和 αvβ5。我们证明,在已建立的原位 ccRCC 异种移植模型中,HIF2α 特异性 RNAi 触发器的功能性传递导致 HIF2α 基因沉默和随后的肿瘤生长抑制和退化。摩尔癌症治疗; 17(1); 140-9。©2017 AACR。
更新日期:2017-10-27
down
wechat
bug