Suppression of Prostate Cancer

项目摘要 多达20%的侵袭性前列腺癌具有导致Wnt/β-Catenin上调的突变 发信号。重要的是，最近的分析发现Wnt/β-连环蛋白途径是最重要的不同 耐药个体间的调控途径。我们采用了基于结构的多肽设计 发现能够抑制Wnt/β-Catenin信号转导和前列腺癌细胞的新分子 成长。我们发现大环13是WNT/β-连环蛋白信号的有效抑制因子。在这份提案中，我们概述了 在去势抵抗前列腺癌(CPRC)模型中使用大环13的策略和探索 Wnt/β-Catenin在前列腺癌中的生物学研究这个项目的基本假设是齐聚物 可以合理地设计大周期来抑制β-连环蛋白/Tcf的相互作用，从而抑制前列腺 癌症肿瘤的生长。我们的具体目标是：1)体内检测大环13对-连环蛋白/Tcf的抑制作用 侵袭性前列腺癌模型和2)确定大环13/β-连环蛋白结合特性。 总之，我们希望我们研究目标的完成将为WNT/β提供新的分子洞察- 前列腺癌中的连环蛋白信号转导。

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.