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Targeting Tumor Angiogenesis with G-Quadruplex Binders

使用 G-四联体结合剂靶向肿瘤血管生成

基本信息

批准号：
7216713
负责人：
DAEKYU SUN
金额：
$ 26.03万
依托单位：
UNIVERSITY OF ARIZONA
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：
2006-04-01 至 2011-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7216713
关键词：
Angiogenesis Inhibitors Binding Biochemical Biochemistry Biological Assay Blood capillaries Cell Culture System Cells Cellular biology Chemicals Class Clinical Research DNA Structure Drug Delivery Systems Elements Endothelial Cells Evaluation G-Quartets Gene Expression Regulation Gene Structure Genes Genetic Transcription Genitourinary system Growth Factor Helix (Snails)Human Hypoxia Hypoxia Inducible Factor Imaging Techniques In Vitro Lead Malignant Neoplasms Malignant neoplasm of kidney Mediating Microarray Analysis Migration Assay Mutation Analysis Nude Mice Oncologist Permeability Play Pre-Clinical Model Principal Investigator Process Promoter Regions Protein Overexpression Regulation Renal carcinoma Reporter Research Personnel Resources Reverse Transcriptase Polymerase Chain Reaction Role Structure System Techniques Testing Therapeutic Transcriptional Activation Tube Tumor Angiogenesis Tumor Suppressor Genes Vascular Endothelial Growth Factors angiogenesis base capillary cytokine drug development ear helix high throughput screening human VEGF protein hypoxia inducible factor 1 in vivo interest migration neoplastic cell novel therapeutics pre-clinical prevent programs promoter protein function response small molecule transcription factor tumor tumor xenograft

项目摘要

DESCRIPTION (provided by applicant): The vascular endothelial growth factor (VEGF) and hypoxia inducible factor (HIF)-la play a pivotal role in tumor angiogenesis. The overall objective of this proposal is to explore a new therapeutic strategy aimed at preventing tumor angiogenesis by repressing the transcription of VEGF and HIF-la genes through targeting G-quadruplex structures formed in the promoter region of these genes with small molecules. The specific aims of this proposal are as follows: (1) To investigate whether G-quadruplex structures are formed in vivo in the promoter regions of VEGF and HIF-la genes in tumor cells and can be targeted with small molecules. (2) To determine the role of G-quadruplex structures in VEGF and HIF-la promoter regions in the regulation of these genes, and how G-quadruplex interactive compounds modulate the regulation of these genes. (3) To explore the potential application of G-quadruplex-interactive agents as a new class of anti-angiogenic agents, which can repress the transcriptional activity of the VEGF and HIF-la genes. (4) To discover new classes of G-quadruplex compounds or new lead compounds based on known classes of G-quadruplex-interactive agents that specifically inhibit the transcriptional activation mediated by the promoter activity of VEGF and HIF-la genes. The formation of G-quadruplex structures in the promoter region of the VEGF and HIF-la genes will be studied by using in vivo chemical and enzymatic probing techniques. We will use mutation analysis and promoter reporter assays to determine the role of G-quadruplex structures formed in the promoter region of these genes. Utilizing multiple RT-PCR, microarray analysis, ChIP assay, bioluminescent imaging techniques, and angiogenesis assays, we will evaluate in vitro and in vivo target selectivity and antiangiogenic activity of G-quadruplex-interactive agents. Lastly, cell free biochemical assays and cell based high-throughput screening system will be utilized to identify other lead compounds that selectively downregulate either VEGF or HIF-la expression in a cell culture system. These studies lead directly to the evaluation of the anti-angiogenic and antitumor effects of G- quadruplex-interactive agents in a preclinical model of human kidney cancer, a tumor type characterized by the abnormal overexpression of HIF-la and VEGF due to the frequent loss of the von Hippel Lindau (VHL) tumor suppressor gene.

描述(申请人提供)：血管内皮生长因子(VEGF)和缺氧诱导因子(HIF)-1a在肿瘤血管生成中起关键作用。这项建议的总体目标是探索一种新的治疗策略，旨在通过用小分子靶向这些基因启动子区域形成的G-四链结构来抑制VEGF和HIF-1a基因的转录，从而防止肿瘤血管生成。本研究的具体目的如下：(1)研究肿瘤细胞中血管内皮生长因子和缺氧诱导因子-1α基因的启动子区域是否存在G-四链结构，并以小分子为靶点。(2)确定血管内皮细胞生长因子和缺氧诱导因子-α启动子区域的G-四链结构在调控这些基因中的作用，以及G-四链相互作用化合物如何调节这些基因的调控。(3)探索G-四链相互作用剂作为一类新型抗血管生成药物的潜在应用，抑制血管内皮生长因子和缺氧诱导因子-1α基因的转录活性。(4)基于已知类型的G-四链相互作用剂，发现新的G-四链化合物或新的先导化合物，特异性地抑制由VEGF和HIF-1α基因启动子活性介导的转录激活。我们将使用体内化学和酶探测技术来研究血管内皮生长因子和缺氧诱导因子-1α基因启动子区域G-四链结构的形成。我们将使用突变分析和启动子报告分析来确定这些基因启动子区域形成的G-四链结构的作用。利用多重RT-PCR、微阵列分析、芯片分析、生物发光成像技术和血管生成实验，我们将在体外和体内评估G-四链相互作用剂的靶向选择性和抗血管生成活性。最后，无细胞生化分析和基于细胞的高通量筛选系统将被用来鉴定在细胞培养系统中选择性下调VEGF或HIF-1a表达的其他先导化合物。这些研究直接导致在人类肾癌的临床前模型中评估G-四链相互作用药物的抗血管生成和抗肿瘤作用。肾癌是一种肿瘤类型，其特征是由于von Hippel Lindau(VHL)肿瘤抑制基因的频繁丢失而导致HIF-1a和VEGF的异常过表达。