Androgen Deprivation Activates Wnt/Beta-Catenin Signaling in Prostate Cancer

总结 雄激素剥夺疗法一直是治疗晚期前列腺疾病的金标准 癌症（PCa）自20世纪60年代以来患者最初对治疗反应良好，导致肿瘤消退，但 最终发展为去势抵抗性前列腺癌，无法治愈。新的抗雄激素药物显示 显著改善雄激素剥夺治疗失败的前列腺癌患者。然而，即使PCa 接受Enzalutamide（最有效的抗雄激素治疗）的患者，最终进展为去势抵抗性 PCa。此外，一旦前列腺癌成为去势抵抗，一个积极的神经内分泌（NE）表型随之而来 发病率高，平均生存期不到1.5年。目前还没有有效 针对具有显著NE表型的PCa的治疗。因此，通过以下方式确定机制： 由于抗雄激素治疗而产生的NE表型对于开发新的抗雄激素治疗是至关重要的。 抗PCa的治疗剂。Wnt/β-连环蛋白信号通路在晚期PCa中普遍存在。我们 先前的研究表明，Wnt/β-连环蛋白信号的激活促进了去势的发展， 具有增加的NE表型的耐药PCa，从而将活性Wnt/β-连环蛋白信号传导与 去势抵抗进展和前列腺癌中NE表型的出现。与此相一致，我们 证实Wnt/β-连环蛋白途径在NEPCa中是活跃的。雄激素缺乏一直是 显示加速前列腺癌中NE表型的出现。我们的初步数据表明， 雄激素剥夺上调Wnt 7a，一种可以激活Wnt/β-连环蛋白信号传导的Wnt配体。我们的数据 也表明雄激素剥夺上调Dkk 1，一种Wnt/β- 连环蛋白信号，在正常前列腺，但不是在前列腺癌。基于这些观察，我们假设， 雄激素剥夺激活Wnt/β-连环蛋白信号传导，促进去势抵抗进展和NE PCa的分化。这一假设将通过以下具体目标进行检验：目标1： 雄激素剥夺激活PCa中的Wnt/β-连环蛋白信号传导。目标2：确定机制 雄激素剥夺通过调节间质/上皮细胞介导的Wnt/β-连环蛋白信号转导， 互动目的3：确定阻断Wnt/β-连环蛋白通路（通过诱导表达 DKK 1和药理学抑制剂）抑制NEPCa。

SUMMARY Androgen deprivation therapy has been the gold standard for the treatment of advanced prostate cancer (PCa) since the 1960s. Patients initially respond well to the treatment resulting in tumor regression, but ultimately progress to castrate-resistant PCa for which there is no cure. New anti-androgens have shown significant improvement in treating PCa patients who failed androgen deprivation therapy. However, even PCa patients on enzalutamide (the most potent anti-androgen therapy), eventually progress to castrate-resistant PCa. Moreover, once PCa becomes castrate-resistant, an aggressive neuroendocrine (NE) phenotype ensue with high morbidity, with only an average survival of less than 1.5 years. There are currently no effective treatments against PCa with a prominent NE phenotype. Therefore, identifying the mechanism(s) through which NE phenotype arises as consequence to anti-androgen therapies is critical for the development of novel therapeutics against PCa. The Wnt/beta-Catenin signaling pathway is prevalent in advanced PCa. We previously showed that activation of Wnt/beta-Catenin signaling promotes the development of castrate- resistant PCa with an increased NE phenotype, thus linking the active Wnt/beta-Catenin signaling with castrate-resistant progression and the emergence of NE phenotype in PCa. Consistent with this, we corroborated that the Wnt/beta-Catenin pathway is active in the NEPCa. Androgen deprivation has been shown to accelerate the emergence of the NE phenotype in PCa. Our preliminary data demonstrated that androgen deprivation upregulated Wnt7a, a Wnt ligand that can activate Wnt/beta-Catenin signaling. Our data also indicated that androgen deprivation upregulated Dkk1, an endogenous secretory inhibitor of the Wnt/beta- Catenin signaling, in normal prostates but not in PCa. Based on these observations, we hypothesize that androgen deprivation activates Wnt/beta-Catenin signaling to promote castrate-resistant progression and NE differentiation of PCa. This hypothesis will be tested by the following Specific Aims: Aim 1: To determine how androgen deprivation activates Wnt/beta-Catenin signaling in PCa. Aim 2: To determine the mechanism(s) through which androgen deprivation modulates Wnt/beta-Catenin signaling by regulating stromal/epithelial interaction. Aim 3: To determine whether blocking the Wnt/beta-Catenin pathway (via inducible expression of DKK1 and pharmacological inhibitors) suppresses NEPCa.