U1 Adaptors Suppress the KRAS-MYC Oncogenic Axis in Human Pancreatic Cancer Xenografts.
U1 Adaptors Suppress the KRAS-MYC Oncogenic Axis in Human Pancreatic Cancer Xenografts.
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DOI：
10.1158/1535-7163.mct-16-0867
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发表时间：
2017-08
影响因子：
5.7
通讯作者：
Carpizo DR
中科院分区：
文献类型：
--
作者：
Tsang AT;Dudgeon C;Yi L;Yu X;Goraczniak R;Donohue K;Kogan S;Brenneman MA;Ho ES;Gunderson SI;Carpizo DR
针对 KRAS 和 MYC 一直是癌症药物开发中的巨大挑战。小鼠模型的遗传学研究已经验证了在突变 KRAS 驱动的肿瘤中沉默 KRAS 和 MYC 表达的功效。我们研究了一种针对 KRAS 和 MYC 的新型寡核苷酸介导的基因沉默技术（U1 适配器）在胰腺癌中的治疗潜力。纳米颗粒与抗 KRAS U1 接头 (U1-KRAS) 的复合物在体外和体内不同的人胰腺癌细胞系中显示出对 KRAS 的显着抑制作用。由于无纳米粒子的方法更容易开发成药物，因此我们通过将 U1 接头与肿瘤靶向肽（iRGD 和 cRGD）缀合来改进 U1 接头的配方。与荧光标记的 U1 接头偶联的肽在体内显示出选择性肿瘤定位。胰腺癌异种移植模型的功效实验显示 iRGD 和 (cRGD)2-KRAS 接头均具有高效 (>90%) 的抗肿瘤活性。靶向 MYC 的 U1 接头可抑制胰腺癌细胞增殖，导致体外细胞凋亡 (40-70%) 和体内肿瘤消退。体内 iRGD 缀合的 U1 KRAS 和 U1 MYC 接头的比较显示，与对照相比，裂解的 caspase-3 染色程度显着更高，而 Ki67 染色则减少。 U1 KRAS 和 U1 MYC 适配器组之间的疗效没有显着差异。我们的结果验证了在胰腺癌治疗中同时靶向 KRAS 和 MYC 的价值，并提供证据表明 U1 Adapter 技术可以使用无纳米颗粒的递送系统成功转化，以靶向癌症中的两个不可成药的基因。
Targeting KRAS and MYC has been a tremendous challenge in cancer drug development. Genetic studies in mouse models have validated the efficacy of silencing expression of both KRAS and MYC in mutant KRAS driven tumors. We investigated the therapeutic potential of a new oligonucleotide-mediated gene silencing technology (U1 Adaptor) targeting KRAS and MYC in pancreatic cancer. Nanoparticles in complex with anti-KRAS U1 Adaptors (U1-KRAS) showed remarkable inhibition of KRAS in different human pancreatic cancer cell lines in vitro and in vivo. As a nanoparticle-free approach is far easier to develop into a drug, we refined the formulation of U1 Adaptors by conjugating them to tumor targeting peptides (iRGD and cRGD). Peptides coupled to fluorescently tagged U1 Adaptors showed selective tumor localization in vivo. Efficacy experiments in pancreatic cancer xenograft models showed highly potent (>90%) anti-tumor activity of both iRGD and (cRGD)2-KRAS Adaptors. U1 Adaptors targeting MYC inhibited pancreatic cancer cell proliferation caused apoptosis in vitro (40–70%) and tumor regressions in vivo. Comparison of iRGD conjugated U1 KRAS and U1 MYC Adaptors in vivo revealed a significantly greater degree of cleaved caspase-3 staining and decreased Ki67 staining as compared with controls. There was no significant difference in efficacy between the U1 KRAS and U1 MYC Adaptor groups. Our results validate the value in targeting both KRAS and MYC in pancreatic cancer therapeutics and provide evidence that the U1 Adaptor technology can be successfully translated using a nanoparticle free delivery system to target two undruggable genes in cancer.