Targeted tumor-penetrating siRNA nanocomplexes for credentialing the ovarian cancer oncogene ID4.
Targeted tumor-penetrating siRNA nanocomplexes for credentialing the ovarian cancer oncogene ID4.
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DOI：
10.1126/scitranslmed.3003778
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发表时间：
2012-08-15
影响因子：
17.1
通讯作者：
Bhatia SN
中科院分区：
文献类型：
--
作者：
Ren Y;Cheung HW;von Maltzhan G;Agrawal A;Cowley GS;Weir BA;Boehm JS;Tamayo P;Karst AM;Liu JF;Hirsch MS;Mesirov JP;Drapkin R;Root DE;Lo J;Fogal V;Ruoslahti E;Hahn WC;Bhatia SN
对大量癌症基因组的全面表征最终将导致特定癌症中遗传改变的概要。不幸的是，鉴定的改变的数量和复杂性使鉴定对肿瘤维持至关重要的生物学相关突变的努力复杂化，因为这些靶点中的许多不适合小分子或抗体的操纵。RNAi提供了一种直接的方法来研究假定的癌症靶点;然而，将治疗剂特异性递送到肿瘤实质仍然是一个棘手的问题。我们描述了一个用于发现和初步验证癌症靶点的平台，该平台由系统性努力组成，以识别人类癌细胞系和肿瘤中的扩增和必需基因，并与新型模块化递送技术合作。我们开发了一种肿瘤穿透纳米复合物（TPN），由siRNA与串联的肿瘤穿透和膜转位肽复合组成，其能够将siRNA特异性递送到肿瘤实质深处。我们采用TPN在体内评价DNA结合抑制因子4（ID 4）作为一种新的癌基因。用ID 4特异性TPN治疗卵巢肿瘤荷瘤小鼠可抑制已建立肿瘤的生长，并显著提高生存率。这些观察结果不仅证明ID 4是32%的高级别卵巢癌中的癌基因，而且还为识别，验证和理解潜在的治疗癌症靶点提供了框架。
The comprehensive characterization of a large number of cancer genomes will eventually lead to a compendium of genetic alterations in specific cancers. Unfortunately, the number and complexity of identified alterations complicate endeavors to identify biologically relevant mutations critical for tumor maintenance, because many of these targets are not amenable to manipulation by small molecules or antibodies. RNAi provides a direct way to study putative cancer targets; however, specific delivery of therapeutics to the tumor parenchyma remains an intractable problem. We describe a platform for the discovery and initial validation of cancer targets, composed of a systematic effort to identify amplified and essential genes in human cancer cell lines and tumors partnered with a novel modular delivery technology. We developed a tumor-penetrating nanocomplex (TPN) comprised of siRNA complexed with a tandem tumor-penetrating and membrane-translocating peptide, which enabled the specific delivery of siRNA deep into the tumor parenchyma. We employed TPN in vivo to evaluate inhibitor of DNA binding 4 (ID4) as a novel oncogene. Treatment of ovarian tumor-bearing mice with ID4-specific TPN suppressed growth of established tumors and significantly improved survival. These observations not only credential ID4 as an oncogene in 32% of high-grade ovarian cancers, but also provide a framework for the identification, validation, and understanding of potential therapeutic cancer targets.
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影响因子：
46.9
作者：
Judge, AD;Sood, V;MacLachlan, I
通讯作者：
MacLachlan, I
影响因子：
11.2
作者：
Fogal V;Zhang L;Krajewski S;Ruoslahti E
通讯作者：
Ruoslahti E
影响因子：
28.2
作者：
Cheung HW;Du J;Boehm JS;He F;Weir BA;Wang X;Butaney M;Sequist LV;Luo B;Engelman JA;Root DE;Meyerson M;Golub TR;Jänne PA;Hahn WC
通讯作者：
Hahn WC
影响因子：
11.4
作者：
Ono, R.;Kumagai, H.;Nosaka, T.
通讯作者：
Nosaka, T.
影响因子：
46.9
作者：
Henke, Erik;Perk, Jonathan;Benezra, Robert
通讯作者：
Benezra, Robert