Graff Jeremy R, Konicek Bruce W, Vincent Thomas M, Lynch Rebecca L, Monteith David, Weir Spring N, Schwier Phil, Capen Andrew, Goode Robin L, Dowless Michele S, Chen Yuefeng, Zhang Hong, Sissons Sean, Cox Karen, McNulty Ann M, Parsons Stephen H, Wang Tao, Sams Lillian, Geeganage Sandaruwan, Douglass Larry E, Neubauer Blake Lee, Dean Nicholas M, Blanchard Kerry, Shou Jianyong, Stancato Louis F, Carter Julia H, Marcusson Eric G
Lilly Research Labs, Eli Lilly and Company, Indianapolis, Indiana 46285, USA.
J Clin Invest. 2007 Sep;117(9):2638-48. doi: 10.1172/JCI32044.
Expression of eukaryotic translation initiation factor 4E (eIF4E) is commonly elevated in human and experimental cancers, promoting angiogenesis and tumor growth. Elevated eIF4E levels selectively increase translation of growth factors important in malignancy (e.g., VEGF, cyclin D1) and is thereby an attractive anticancer therapeutic target. Yet to date, no eIF4E-specific therapy has been developed. Herein we report development of eIF4E-specific antisense oligonucleotides (ASOs) designed to have the necessary tissue stability and nuclease resistance required for systemic anticancer therapy. In mammalian cultured cells, these ASOs specifically targeted the eIF4E mRNA for destruction, repressing expression of eIF4E-regulated proteins (e.g., VEGF, cyclin D1, survivin, c-myc, Bcl-2), inducing apoptosis, and preventing endothelial cells from forming vessel-like structures. Most importantly, intravenous ASO administration selectively and significantly reduced eIF4E expression in human tumor xenografts, significantly suppressing tumor growth. Because these ASOs also target murine eIF4E, we assessed the impact of eIF4E reduction in normal tissues. Despite reducing eIF4E levels by 80% in mouse liver, eIF4E-specific ASO administration did not affect body weight, organ weight, or liver transaminase levels, thereby providing the first in vivo evidence that cancers may be more susceptible to eIF4E inhibition than normal tissues. These data have prompted eIF4E-specific ASO clinical trials for the treatment of human cancers.
真核生物翻译起始因子4E（eIF4E）的表达在人类癌症和实验性癌症中通常会升高，促进血管生成和肿瘤生长。eIF4E水平升高会选择性地增加在恶性肿瘤中起重要作用的生长因子（如血管内皮生长因子、细胞周期蛋白D1）的翻译，因此是一个有吸引力的抗癌治疗靶点。然而，迄今为止，尚未开发出eIF4E特异性疗法。在此我们报告了eIF4E特异性反义寡核苷酸（ASO）的研发，这些寡核苷酸被设计成具有全身抗癌治疗所需的必要组织稳定性和核酸酶抗性。在哺乳动物培养细胞中，这些ASO特异性靶向eIF4E mRNA以进行破坏，抑制eIF4E调节蛋白（如血管内皮生长因子、细胞周期蛋白D1、生存素、c-myc、Bcl-2）的表达，诱导细胞凋亡，并阻止内皮细胞形成血管样结构。最重要的是，静脉注射ASO可选择性且显著降低人肿瘤异种移植物中eIF4E的表达，显著抑制肿瘤生长。由于这些ASO也靶向鼠类eIF4E，我们评估了eIF4E减少对正常组织的影响。尽管在小鼠肝脏中eIF4E水平降低了80%，但给予eIF4E特异性ASO并不影响体重、器官重量或肝脏转氨酶水平，从而首次在体内证明癌症可能比正常组织更容易受到eIF4E抑制的影响。这些数据促使开展eIF4E特异性ASO治疗人类癌症的临床试验。
