Suppression of Prostate Cancer

抑制前列腺癌

基本信息

批准号：
10684749
负责人：
Susan K. Logan
金额：
$ 19.41万
依托单位：
NEW YORK UNIVERSITY SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-01 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10684749
关键词：
Affinity Amino Acids Androgen Antagonists Androgen Receptor Animal Model Binding Binding Sites Biological Assay Biology Cancer Cell Growth Cancer Etiology Castration Cell Culture Techniques Cell model Cessation of life Characteristics DNA-Binding Proteins Disease Disease Progression Drug Design Drug Kinetics Embryo Generations Genetic Transcription Goals Growth Hybrids In Vitro Individual Life Expectancy Localized Disease Luciferases Malignant Neoplasms Malignant neoplasm of prostate Maps Modeling Molecular Monitor Mus Mutagenesis Mutation N-terminal Pathway interactions Patients Peptides Peptoids Periodicity Pharmacodynamics Pharmacology Pre-Clinical Model Prognosis Proliferating Prostatic Neoplasms Protein Engineering Proteins Protocols documentation Research Resistance Resistance development Signal Transduction Site Structure Surface Survival Rate Testing Up-Regulation WNT Signaling Pathway Xenograft procedure Zebrafish abiraterone beta catenin castration resistant prostate cancer design enzalutamide in vivo in vivo Model inhibitor insight men novel therapeutic intervention peptidomimetics prostate cancer cell protein protein interaction rational design response small molecule subcutaneous therapeutic target three dimensional cell culture transcription factor tumor tumor growth tumor microenvironment

项目摘要

Project Summary As many as 20% of aggressive prostate cancers have mutations resulting in upregulation of Wnt/β-catenin signaling. Importantly, recent analysis identified the Wnt/β-catenin pathway as the foremost differentially modulated pathway among treatment-resistant individuals. We used structure-based design of peptidomimetic oligomers to discover new molecules capable of inhibiting Wnt/β-catenin signaling and prostate cancer cell growth. We identified macrocycle 13 as a potent inhibitor of Wnt/β-catenin signaling. In this proposal we outline a strategy to use macrocycle 13 in models of castration resistant prostate cancer (CPRC) and to explore the biology of Wnt/β-catenin in prostate cancer. The hypothesis underlying of this project is that oligomer macrocycles can be rationally designed to inhibit the β-catenin/TCF interaction, thereby inhibiting prostate cancer tumor growth. Our specific aims are to 1) test macrocycle 13 inhibition of -catenin/TCF in in vivo models of aggressive prostate cancer and 2) determine macrocycle 13/β-catenin binding characteristics. Altogether, we expect that completion of our research goals will provide new molecular insight into Wnt/β- catenin signaling in prostate cancer.

项目概要多达 20% 的侵袭性前列腺癌存在导致 Wnt/β-连环蛋白上调的突变重要的是，最近的分析确定 Wnt/β-catenin 通路是最重要的差异信号通路。我们使用基于结构的拟肽设计。寡聚物发现能够抑制 Wnt/β-catenin 信号传导和前列腺癌细胞的新分子我们确定大环 13 是 Wnt/β-连环蛋白信号传导的有效抑制剂。在去势抵抗性前列腺癌 (CPRC) 模型中使用大环化合物 13 的策略并探索 Wnt/β-连环蛋白在前列腺癌中的生物学作用该项目的假设是寡聚物。合理设计大环化合物可抑制β-catenin/TCF相互作用，从而抑制前列腺我们的具体目标是 1) 体内测试大环 13 对 β-连环蛋白/TCF 的抑制作用。侵袭性前列腺癌模型，2) 确定大环 13/β-连环蛋白结合特征。总而言之，我们预计研究目标的完成将为 Wnt/β- 提供新的分子见解前列腺癌中的连环蛋白信号传导。