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.

项目摘要多达20％的侵略性前列腺癌具有突变，导致Wnt/β-catenin上调信号。重要的是，最近的分析确定Wnt/β-catenin途径是最重要的对治疗的个体之间的调节途径。我们使用了基于结构的辣妹设计低聚物发现能够抑制Wnt/β-catenin信号传导和前列腺癌细胞的新分子生长。我们将大环13鉴定为Wnt/β-catenin信号传导的潜在抑制剂。在此提案中，我们概述了一种在抑制前列腺癌（CPRC）模型中使用大环13的策略，并探索前列腺癌中Wnt/β-catenin的生物学。该项目的基础假设是低聚物大环的理性设计可以抑制β-catenin/tcf相互作用，从而抑制前列腺癌症肿瘤的生长。我们的具体目的是1）测试大环13在体内抑制-catenin/tcf 攻击性前列腺癌的模型和2）确定大环13/β-catenin结合特征。总的来说，我们预计我们的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Catenin信号传导。