Targeting Wnt-dependent colorectal cancer

WNT信号传导的组成性激活驱动了一系列人类肿瘤的生长，包括近 所有结肠直肠癌（CRC）。尽管如此突出，但目前没有Wnt抑制剂被批准用于临床应用。 使用.缺乏抑制剂的主要原因是缺乏可药用的WNT途径组分， 在动物模型中观察到许多候选抑制剂的靶向胃肠道（GI）毒性。我们 未发表的结果表明，Wnt负调节因子酪蛋白激酶1α（CK1α）的表达减少， 信号传导与CRC患者的存活率降低相关。这些发现证实了CK1α作为一种药物 CRC的目标。因此，我们表征了一种新的小分子CK1α激活剂SSTC 3， 这将使我们能够在体内靶向CK1α。SSTC 3在体外减弱CRC生长 在体内，延长小鼠结直肠肿瘤模型的存活，抑制CRC的生长， 异种移植重要的是，SSTC 3没有表现出显著的GI毒性。因此，CK1α是一种真正的药物， 在CRC中的靶点，其激活抑制肿瘤发生而不诱导具有 阻碍了Wnt抑制剂的临床开发。尽管有这样的承诺，许多机械问题 关于这类新的Wnt抑制剂，我们将开始在这里讨论。我们特别 建议i）确定这类小分子如何激活CK1α活性，ii）确定 CK1α底物，驱动其疗效，但限制其对正常GI稳态的影响，和iii）开发生物标志物 这可以用来确定那些CRC患者最有可能对这些抑制剂产生有利的反应。

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 Our unpublished results show that reduced expression of Casein Kinase 1α (CK1α), a negative regulator of Wnt signaling, is associated with decreased survival of CRC patients.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.