Targeting Tumor Angiogenesis with G-Quadruplex Binders

Project: Research project

Description

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.
StatusFinished
Effective start/end date4/1/062/28/12

Funding

  • National Institutes of Health: $260,253.00
  • National Institutes of Health: $51,840.00
  • National Institutes of Health: $260,253.00
  • National Institutes of Health: $54,629.00
  • National Institutes of Health: $267,803.00
  • National Institutes of Health: $53,213.00
  • National Institutes of Health: $260,253.00
  • National Institutes of Health: $260,253.00

Fingerprint

G-Quadruplexes
Vascular Endothelial Growth Factor A
Genetic Promoter Regions
Neoplasms
Genes
Luminescent Measurements
Hypoxia
Kidney Neoplasms
Microarray Analysis
Tumor Suppressor Genes
Transcriptional Activation
Down-Regulation
Cell Culture Techniques

ASJC

  • Medicine(all)