Targeting Wnt-dependent colorectal cancer

靶向 Wnt 依赖性结直肠癌

• 批准号: 10358499
• 负责人: DAVID J ROBBINS
• 金额: $ 35.47万
• 依托单位: GEORGETOWN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-12 至 2024-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10358499
• 关键词: Address; Agonist; American; Animal Model; Attenuated; Binding; Bioinformatics; Biological Markers; CSNK1A1 gene; Cancerous; Cell Line; Cell Survival; Cells; Clinical; Colorectal Cancer; Colorectal Neoplasms; Data; Docking; Dose-Limiting; Drug Kinetics; Engineering; Event; Exposure to; Family member; Genetic Transcription; Genomics; Goals; Growth; Human; In Vitro; Link; Malignant Neoplasms; Modeling; Mus; Mutation; Organoids; Pathway interactions; Pharmacology; Process; Property; Proteins; Regulation; Signal Transduction; Structure; Therapeutic; Therapeutic Index; Tissues; Toxic effect; WNT Signaling Pathway; Xenograft procedure; base; cancer cell; casein kinase; clinical development; colon cancer cell line; colon cancer patients; colorectal cancer progression; druggable target; gastrointestinal; genomic data; in vivo; inhibitor; intestinal homeostasis; molecular modeling; next generation; novel; predictive marker; small molecule; tumor; tumorigenesis

Constitutive activation of WNT signaling drives the growth of a broad array of human tumors, including nearly all colorectal cancers (CRCs). Despite this prominence, no Wnt inhibitors are currently approved for clinical use. The major reasons for this lack of inhibitors are the paucity of druggable WNT pathway components and the on-target gastrointestinal (GI) toxicity observed in animal models with many candidate inhibitors. Our unpublished results show that reduced expression of Casein Kinase 1α (CK1α), a negative regulator of Wnt signaling, is associated with decreased survival of CRC patients. These findings validate CK1α as a druggable target in CRC. We therefore characterized a novel, small molecule activator of CK1α, SSTC3, with pharmacokinetic properties that would allow us to target CK1α in vivo. SSTC3 attenuated CRC growth in vitro and in vivo, prolonging the survival of a mouse colorectal tumor model and inhibiting the growth of CRC xenografts. Importantly, SSTC3 did not exhibit significant GI toxicity. Thus, CK1α is a bona fide druggable target in CRC, activation of which inhibits tumorigenesis without inducing the GI toxicity that has hampered the clinical development of Wnt inhibitors. Despite this promise, many mechanistic questions remain regarding this novel class of Wnt inhibitors, which we will begin to address here. Specifically, we propose to i) determine how this class of small-molecules functions to activate CK1α activity, ii) identify the CK1α substrates that drive its efficacy but limit its effect on normal GI homeostasis, and iii) develop biomarkers that could be used to identify those CRC patients most likely to respond favorably to such inhibitors.

WNT信号的结构性激活推动了广泛的人类肿瘤的生长，包括近 所有结直肠癌(CRC)。尽管如此，目前还没有Wnt抑制剂被批准用于临床 使用。缺乏抑制剂的主要原因是缺乏可用药的WNT途径成分和 在使用多种候选抑制剂的动物模型中观察到的靶向胃肠道(GI)毒性。我们的 未发表的结果表明，Wnt的负调控因子酪蛋白激酶1α(CK1α)的表达减少 信号转导，与结直肠癌患者存活率降低有关。这些发现证实了CK1α是一种可用药 目标在CRC。因此，我们鉴定了一种新型的CK1α的小分子激活剂SSTC3，它具有 药代动力学特性，使我们能够在体内靶向CK1α。SSTC3抑制结直肠癌生长的实验研究 在体内，延长小鼠结直肠癌模型的存活时间并抑制结直肠癌的生长 异种移植物。重要的是，SSTC3没有表现出明显的胃肠道毒性。因此，CK1α是一种真正的可用药 结直肠癌的靶标，其激活可抑制肿瘤的发生，而不会引起胃肠道毒性 阻碍了Wnt抑制剂的临床发展。尽管有这样的承诺，许多机械性的问题 关于这类新颖的WnT抑制剂，我们将在这里开始讨论。具体来说，我们 建议i)确定这类小分子如何作用于激活ck1α活性，ii)确定 驱动其疗效但限制其对正常胃肠道稳态影响的CK1α底物，以及iii)开发生物标记物 这可以用来识别哪些结直肠癌患者对这种抑制剂最有可能产生积极的反应。