Tumor-Targeting Oligonucleotides

肿瘤靶向寡核苷酸

• 批准号: 7662572
• 负责人: Paula J. Bates
• 金额: $ 25.51万
• 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/7662572
• 关键词: Adopted; Advanced Malignant Neoplasm; Adverse effects; Affinity; Antisense Oligonucleotides; Base Sequence; Binding; Cancer Detection; Cancer Patient; Cancer cell line; Cell Death; Cell Nucleolus; Cell surface; Cells; Chemicals; Classification; Clinical; Clinical Trials; Development; Disease; Endothelial Cells; Evolution; G-Quartets; Goals; Hand; Image; In complete remission; Individual; Lead; Libraries; Ligands; Malignant Neoplasms; Mediating; Methods; Modification; Monoclonal Antibodies; Mus; Names; Normal Cell; Nucleic acid sequencing; Oligonucleotides; Patients; Peptides; Pharmaceutical Preparations; Phase I Clinical Trials; Play; Principal Investigator; Procedures; Process; Proliferating; Property; Protein Binding; Proteins; RNA; Radioisotopes; Recombinants; Reporting; Research Personnel; Resistance; Role; Serum; Small Interfering RNA; Specific qualifier value; Structure; Surface; Techniques; Testing; Therapeutic; Therapeutic Clinical Trial; Toxic effect; Tumor Tissue; Vertebral column; Xenograft procedure; anticancer activity; anticancer research; aptamer; base; cancer cell; cancer therapy; cell type; chemotherapy; combinatorial; design; improved; in vivo; insight; interest; malignant breast neoplasm; nanoparticle; neoplastic cell; novel; novel strategies; nuclease; nucleolin; phosphodiester; phosphorothioate; preclinical study; programs; protein function; protein structure; synthetic construct; tumor; tumorigenesis; uptake

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）：转化癌症研究的一个主要目标是开发靶向治疗，可以特异性抑制在肿瘤发生中起重要作用的蛋白质的表达或功能。使用合成的DNA或RNA寡核苷酸来实现这一目标具有相当大的兴趣，因为它们能够以高亲和力识别特定的核酸序列或蛋白质结构。几种基于阿糖胞苷的策略，包括反义、小干扰RNA（siRNA）、蛋白结合适体和免疫刺激寡核苷酸，在临床前研究中产生了有效的抗癌作用。然而，治疗性（反义）寡核苷酸的临床试验通常令人失望，这部分归因于它们被癌细胞的低效摄取。主要研究者和她的合作者开发了一种名为AGRO 100的新型抗增殖寡核苷酸。这种分子最近在涉及晚期癌症患者的临床试验中进行了测试，并显示出明显缺乏毒性和有希望的临床活性。与大多数其他寡核苷酸不同，AGRO 100在培养和体内被癌细胞有效且选择性地吸收。我们假设这些非凡的特性与AGR 0100的不寻常的G-四链体结构及其特异性结合癌细胞表面高水平表达的蛋白质的能力有关。该项目的长期目标是开发被体内癌症贪婪和选择性吸收的寡核苷酸。这样的肿瘤靶向序列可以被掺入基于阿托伐他汀的治疗剂中或与化疗药物缀合，以增强其功效并减少令人不快的副作用。在本申请中，我们建议阐明AGRO 100的优先摄取肿瘤所涉及的机制，并确定序列或结构基序，导致有效的寡核苷酸内化的癌细胞。第一个具体目标是表征AGRO 100的细胞内化，并确认核仁素在这一过程中的作用。第二个目的是使用SELEX方法来鉴定具有被癌细胞有效和选择性摄取的寡核苷酸（来自组合文库）。第三个目的是将最佳的肿瘤靶向序列掺入反义、siRNA和免疫调节寡核苷酸中，以确定这是否导致上级摄取和活性。