Tumor-Targeting Oligonucleotides

肿瘤靶向寡核苷酸

基本信息

批准号：
7906006
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
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-08-01 至 2012-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7906006
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 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

项目摘要

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疗法，这些疗法可以专门抑制蛋白质的表达或功能，这些蛋白质在肿瘤发生中起着至关重要的作用。由于它们能够识别具有高亲和力的指定核酸序列或蛋白质结构的能力，因此对使用合成DNA或RNA寡核苷酸来实现这一目标有很大的兴趣。几种基于寡核苷酸的策略，包括反义，小干扰RNA（siRNA），蛋白质结合的适体和免疫刺激性寡核苷酸，在临床前研究中产生了有效的抗癌作用。然而，治疗（反义）寡核苷酸的临床试验通常令人失望，这部分归因于癌细胞效率低下的摄取。首席研究员及其合作者开发了一种新型的抗增生性寡核苷酸Agro100。该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，并且表现出显着缺乏毒性以及有希望的临床活性。与大多数其他寡核苷酸不同，Agro100在培养物和体内有效地被癌细胞有效地吸收。我们假设这些非凡的特性与AgR0100的异常G四链体结构及其与癌细胞表面高水平表达的蛋白质结合的能力。该项目的长期目标是开发寡核苷酸，这些寡核苷酸被体内癌症狂热和有选择地吸收。这种靶向肿瘤的序列可以纳入基于寡核苷酸的疗法中，也可以与化学疗法药物共轭，以增强其功效并降低不愉快的副作用。在此应用中，我们建议阐明肿瘤对Agro100的优先吸收的机制，并鉴定导致癌细胞有效寡核苷酸内在化的序列或结构基序。第一个具体目的是表征Agro100的细胞内在化并确认核仁在此过程中的作用。第二个目的是使用SELEX方法来鉴定具有有效且选择性摄取癌细胞的寡核苷酸（来自组合文库）。第三个目的是将最佳肿瘤靶向序列纳入反义，siRNA和免疫调节性寡核苷酸中，以确定这是否导致了出色的摄取和活性。

项目成果

期刊论文数量（5）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Mechanistic studies of anticancer aptamer AS1411 reveal a novel role for nucleolin in regulating Rac1 activation.

DOI：
10.1016/j.molonc.2015.03.012
发表时间：
2015-08
期刊：
Molecular oncology
影响因子：
6.6
作者：
Reyes-Reyes EM;Šalipur FR;Shams M;Forsthoefel MK;Bates PJ
通讯作者：
Bates PJ

AS1411-conjugated gold nanospheres and their potential for breast cancer therapy.

DOI：
10.18632/oncotarget.4207
发表时间：
2015-09-08
期刊：
Oncotarget
影响因子：
0
作者：
Malik MT;O'Toole MG;Casson LK;Thomas SD;Bardi GT;Reyes-Reyes EM;Ng CK;Kang KA;Bates PJ
通讯作者：
Bates PJ

Cancer-selective antiproliferative activity is a general property of some G-rich oligodeoxynucleotides.