WNT5a/ROR2-Mediated Hippo Pathway Activation in Prostate Cancer

前列腺癌中 WNT5a/ROR2 介导的 Hippo 通路激活

• 批准号: 10734173
• 负责人: Steven P. Balk
• 金额: $ 39.55万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-06-01 至 2028-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10734173
• 关键词: Agonist; Androgens; Binding; Biological Markers; CYP17A1 gene; Cancer Etiology; Carboplatin; Cessation of life; Clinical; Clinical Trials; Complex; DNA Damage; Data; Defect; Family; Feedback; GNRH1 gene; Generations; Growth; Ligand Binding; Link; Malignant Neoplasms; Malignant neoplasm of prostate; Mediating; Mediator; Molecular; Neuroendocrine Prostate Cancer; Neurofibromin 2; Nuclear; Pathway interactions; Patients; Pharmaceutical Preparations; Physiological; Poly(ADP-ribose) Polymerase Inhibitor; Prognosis; Prostate; Prostate Cancer therapy; Proteins; ROR1 gene; Reporting; Resistance; Sampling; Signal Pathway; Signal Transduction; Solid Neoplasm; Testing; Therapeutic; Tumor Promotion; WNT Signaling Pathway; abiraterone; androgen deprivation therapy; antagonist; beta catenin; biomarker identification; castration resistant prostate cancer; deprivation; effective therapy; efficacy evaluation; enzalutamide; inhibitor; link protein; men; mimetics; novel; patient derived xenograft model; planar cell polarity; predict responsiveness; receptor; resistance mechanism; response; restraint; standard of care; taxane; transcription factor; tumor

Androgen deprivation remains the standard systemic treatment for prostate cancer (PCa) that has spread beyond the prostate, but most patients progress to metastatic castration-resistant prostate cancer (mCRPC). Many of these tumors will respond to abiraterone or to second generation AR antagonists, but resistance inevitably develops. Some patients at this stage may respond to taxanes or to PARP inhibitors, but options for the majority of patients are limited. Increased Wnt signaling is one of the mechanisms that has been implicated in the progression to ASI resistance. The canonical Wnt/β-catenin pathway is initiated when a Wnt ligand binds to a Frizzled family receptor, which results in increased β-catenin and coactivation of TCF family transcription factors. A subset of Wnts can preferentially activate noncanonical Wnt pathways through receptors including ROR1 and ROR2. The downstream signaling pathways are less well-defined and are context dependent, but include the planar cell polarity and Wnt-Ca++ pathways. Notably, noncanonical Wnt signaling has also been reported to inhibit the tumor suppressive Hippo pathway, thereby enhancing the nuclear expression of YAP1 and TAZ, with subsequent stimulation of the TEAD-family transcription factors. Wnt5a is the predominant noncanonical Wnt whose expression is often dysregulated in cancer, and it has been implicated in both tumor- suppressive and tumor-promoting activities. In PCa, increased Wnt5a expression has been associated with mCRPC and with neuroendocrine PCa, but has also been associated with better prognosis in localized PCa, and with growth suppression and dormancy. While these studies indicate that noncanonical Wnt signaling can have growth suppressive as well as stimulatory effects, the downstream signals mediating these effects remain to be established. We have found that the growth suppressive effects of Wnt5a in PCa are mediated through ROR2, and that this Wnt5a/ROR2 signaling is activating the Hippo pathway to suppress YAP1/TAZ activity. While Wnt signaling has been linked to suppression of the Hippo pathway, our studies are the first to show it can activate Hippo and provide a mechanism for the growth suppressing effects of Wnt5a. We hypothesize this reflects a novel function of ROR2 that is context dependent, and that biomarkers can be identified that will identify the subset of tumors that will be responsive to Wnt5a-mimetic drugs such as Foxy5, which is currently in clinical trials. The central hypotheses of this proposal are that Wnt5a-mimetic drugs that drive noncanonical Wnt signaling can be an effective treatment for a subset of mCRPC (and other solid tumors), that their growth suppressive effects are through Hippo pathway activation, and that this reflects a physiological negative feedback loop to restrain YAP1/TAZ activity. The objectives are to determine the molecular basis for Wnt5a- mediated activation of the Hippo pathway (Aim 1) and to assess the therapeutic potential of stimulating this pathway, including the identification of biomarkers that can predict which tumors may respond to available Wnt5a-mimetic drugs (Aim 2).

雄激素剥夺仍然是已扩散的前列腺癌 (PCa) 的标准全身治疗 但大多数患者会进展为转移性去势抵抗性前列腺癌 (mCRPC)。 许多这些肿瘤会对阿比特龙或第二代 AR 拮抗剂产生反应，但耐药性 不可避免地发展。此阶段的一些患者可能对紫杉烷类药物或 PARP 抑制剂有反应，但可选择 大多数患者的能力有限。 Wnt 信号传导增加是所涉及的机制之一 进展为 ASI 抵抗。当 Wnt 配体结合时，经典的 Wnt/β-连环蛋白途径就会启动 与卷曲家族受体结合，导致 β-连环蛋白增加和 TCF 家族转录共激活 因素。 Wnt 的一个子集可以优先通过受体激活非经典 Wnt 通路，包括 ROR1 和 ROR2。下游信号通路不太明确并且依赖于上下文，但是 包括平面细胞极性和 Wnt-Ca++ 途径。值得注意的是，非规范的 Wnt 信号传导也已被 据报道可抑制肿瘤抑制 Hippo 通路，从而增强 YAP1 和 TAZ，随后刺激 TEAD 家族转录因子。 Wnt5a 占主导地位 非经典 Wnt 的表达在癌症中经常失调，并且与肿瘤和肿瘤相关。 抑制和促进肿瘤的活性。在 PCa 中，Wnt5a 表达增加与 mCRPC 与神经内分泌 PCa 相关，但也与局部 PCa 的更好预后相关， 并具有生长抑制和休眠作用。虽然这些研究表明非经典 Wnt 信号传导可以 具有生长抑制和刺激作用，介导这些作用的下游信号仍然存在 待成立。我们发现 Wnt5a 在 PCa 中的生长抑制作用是通过 ROR2，并且该 Wnt5a/ROR2 信号传导正在激活 Hippo 通路以抑制 YAP1/TAZ 活性。 虽然 Wnt 信号传导与 Hippo 通路的抑制有关，但我们的研究首次表明它可以 激活 Hippo 并提供 Wnt5a 生长抑制作用的机制。我们假设这个 反映了 ROR2 的一种新功能，该功能是上下文相关的，并且可以识别生物标志物来识别 对 Wnt5a 模拟药物（例如目前正处于临床阶段的 Foxy5）有反应的肿瘤子集 试验。该提案的中心假设是驱动非经典 Wnt 的 Wnt5a 模拟药物 信号转导可以成为 mCRPC（和其他实体瘤）子集的有效治疗方法，它们的生长 抑制作用是通过 Hippo 通路激活实现的，这反映了生理上的负面影响 反馈回路抑制 YAP1/TAZ 活性。目标是确定 Wnt5a- 的分子基础 介导 Hippo 通路激活（目标 1）并评估刺激该通路的治疗潜力 途径，包括识别可以预测哪些肿瘤可能对现有药物产生反应的生物标志物 Wnt5a 模拟药物（目标 2）。