Tumor-Targeting Oligonucleotides

肿瘤靶向寡核苷酸

• 批准号: 7132949
• 负责人: Paula J. Bates
• 金额: $ 26.27万
• 依托单位: UNIVERSITY OF LOUISVILLE
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-08-01 至 2011-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7132949
• 关键词: neoplasm /cancer; neoplastic cell; oligonucleotides

DESCRIPTION (provided by applicant): A major goal of translational cancer research is to develop targeted therapies that can specifically inhibit the expression or function of proteins that play an essential role in oncogenesis. There is considerable interest in using synthetic DNA or RNA oligonucleotides to achieve this goal because of their ability to recognize specified nucleic acid sequences or protein structures with high affinity. Several oligonucleotide-based strategies, including antisense, small interfering RNAs (siRNAs), protein-binding aptamers and immunostimulatory oligonucleotides, have produced potent anti-cancer effects in pre-clinical studies. However, clinical trials of therapeutic (antisense) oligonucleotides have been generally disappointing and this has been attributed, in part, to their inefficient uptake by cancer cells. The Principal Investigator and her collaborators have developed a novel antiproliferative oligonucleotide named AGRO100. This molecule has recently been tested in a clinical trial involving patients with advanced cancer and has demonstrated a remarkable lack of toxicity combined with promising clinical activity. Unlike most other oligonucleotides, AGRO100 is taken up efficiently and selectively by cancer cells in culture and in vivo. We hypothesize that these extraordinary properties are related to the unusual G-quadruplex structure of AGR0100 and its ability to bind specifically to a protein that is expressed at high levels on the surface of cancer cells. The long-term goal of this project is to develop oligonucleotides that are avidly and selectively taken up by cancers in vivo. Such tumor-targeting sequences could be incorporated into oligonucleotide-based therapeutics or conjugated to chemotherapy drugs in order to enhance their efficacy and reduce unpleasant side effects. In this application, we propose to elucidate the mechanism involved in the preferential uptake of AGRO100 by tumors and to identify sequence or structural motifs that lead to efficient oligonucleotide internalization by cancer cells. The first specific aim is to characterize the cellular internalization of AGRO100 and confirm the role of nucleolin in this process. The second aim is to use a SELEX approach to identify oligonucleotides (from combinatorial libraries) that have efficient and selective uptake by cancer cells. The third aim is to incorporate the optimal tumor-targeting sequences into antisense, siRNA and immunomodulatory oligonucleotides in order to determine if this leads to superior uptake and activity.

描述(由申请人提供)：转化型癌症研究的一个主要目标是开发有针对性的治疗方法，专门抑制在肿瘤发生中起关键作用的蛋白质的表达或功能。由于人工合成的DNA或RNA寡核苷酸能够识别特定的核酸序列或具有高亲和力的蛋白质结构，因此人们对利用它们来实现这一目标有相当大的兴趣。几种基于寡核苷酸的策略，包括反义、小干扰RNA(SiRNAs)、蛋白结合适体和免疫刺激寡核苷酸，在临床前研究中已经产生了强大的抗癌效果。然而，治疗性(反义)寡核苷酸的临床试验普遍令人失望，这在一定程度上被归因于癌细胞对它们的摄取效率低下。首席研究员和她的合作者开发了一种名为AGRO100的新型抗增殖寡核苷酸。这种分子最近在一项涉及晚期癌症患者的临床试验中进行了测试，并显示出明显的无毒性和良好的临床活性。与大多数其他寡核苷酸不同，AGRO100在培养和体内被癌细胞高效和选择性地摄取。我们推测，这些非凡的特性与AGR0100不寻常的G-四链结构以及它与癌细胞表面高水平表达的蛋白质特异性结合的能力有关。该项目的长期目标是开发可被体内癌症贪婪和选择性摄取的寡核苷酸。这种肿瘤靶向序列可以被整合到基于寡核苷酸的治疗药物中，或者与化疗药物结合，以提高其疗效并减少不良副作用。在这一应用中，我们建议阐明肿瘤优先摄取AGRO100的机制，并确定导致癌细胞有效内化寡核苷酸的序列或结构基序。第一个具体目标是表征AGRO100的细胞内化，并确认核仁素在这一过程中的作用。第二个目标是使用SELEX方法来识别(从组合文库中)具有有效和选择性地被癌细胞摄取的寡核苷酸。第三个目标是将最佳的肿瘤靶向序列整合到反义、siRNA和免疫调节寡核苷酸中，以确定这是否会导致更好的摄取和活性。