Therapeutic targeting of Wnt signaling in cancer

项目摘要/摘要 我们研究计划的首要目标是开发小分子抗癌药物。我们将重点放在这里 一种新的化学方法控制异常的Wnt/β-Catenin信号导致肿瘤的发生和发展 许多癌症的转移，特别是结直肠癌(CRC)。大约4%的人口受到儿童疾病的影响。 并在2021年造成约6万人死亡。尽管经过了几十年的努力，抑制这一致癌途径并没有 成功。2009年，我们首次报道了Wnt/β-catenin信号可以被小分子截获 分子。Tankyrase的催化抑制阻止了Axin的周转，从而导致快速的 轴突的积聚。积累的轴蛋白然后稳定β-连环蛋白破坏复合体(DC)，以促进 β-连环蛋白的降解。然而，使用这种策略治疗癌症并不成功。近期 研究表明，反常的是，tankyrase可以通过分子支持Wnt/β-catenin信号 脚手架。出乎意料的两种行动模式潜在地解释了 Tankyrase抑制剂的各种临床前研究。尽管Tankyrase维持Wnt/β的机制- 连环蛋白信号转导尚不清楚，越来越多的证据表明，Tankyrase聚集是导致这种现象的原因。 在这项研究中，我们将开发一种化学策略来控制tankyrase的非催化功能。 然后，我们将使用这个新工具来研究tankyrase如何影响DC的动态组装。我们将进一步使用 用蛋白质组学方法详细描述Tankyrase的催化和支架功能 他们的行动模式的特征。这项工作将帮助我们理解tankyrase是如何控制多个 对癌症很重要的信号通路。此外，我们将比较一个大型小组的响应性 永生化人结肠上皮细胞系和结直肠癌细胞系的Tankyrase抑制和耗竭。 然后，我们将用体内研究来证实这一结果。细胞的敏感度与它们的基因 研究背景将提供潜在的生物标志物，并为癌症的治疗策略提供参考。总体而言，这个项目 将解决在给Wnt/β-连环蛋白途径下药方面尚未解决的问题，并提高我们对如何 Tankyrase控制Wnt/β-catenin信号转导。

Project Summary/Abstract The overarching goal of our research program is to develop small-molecule anticancer drugs. We focus herein on a new chemical method to control aberrant Wnt/β-catenin signaling that drives tumorigenesis and metastasis of many cancers, in particular, colorectal cancer (CRC). CRC affects about 4% of the population and caused ~60,000 deaths in 2021. Despite decades of effort, drugging this oncogenic pathway has not been successful. In 2009, we reported for the first time that Wnt/β-catenin signaling can be intercepted by small molecules. Catalytic inhibition of tankyrases prevents the turnover of the Axin, which leads to a rapid accumulation of Axin. The accumulated Axin then stabilizes the β-catenin destruction complex (DC) to facilitate the degradation of β-catenin. However, using this strategy to treat cancer has not been successful. Recent studies suggest that tankyrases can, paradoxically, support Wnt/β-catenin signaling through molecular scaffolding. The unexpected dichotomous mode of action potentially explains the unsatisfactory outcomes of various preclinical studies of tankyrase inhibitors. Although the mechanism by which tankyrases sustain Wnt/β- catenin signaling is not clear, mounting evidence suggests that the tankyrase aggregation is responsible for it. In this study, we will develop a chemical strategy to control the catalysis-independent function of tankyrases. We will then use this new tool to study how tankyrases affect the dynamic assembly of DC. We will further use a proteomic approach to delineate the catalytic and scaffolding functions of tankyrases with detailed characterization of their mode of action. This work will help us understand how tankyrases control multiple signaling pathways important to cancer. Additionally, we will compare the responsiveness of a large panel of immortalized human colonic epithelial cell lines and CRC cell lines toward tankyrase inhibition and depletion. We will then corroborate the results with in vivo studies. Correlating the cellular sensitivity with their genetic background will provide potential biomarkers and inform therapeutic strategies for cancers. Overall, this project will address the unsolved issue in drugging the Wnt/β-catenin pathway and improve our understanding of how tankyrases control Wnt/β-catenin signaling.