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).

雄激素剥夺仍然是前列腺癌（PCa）的标准全身治疗， 除了前列腺，但大多数患者进展为转移性去势抵抗性前列腺癌（mCRPC）。 这些肿瘤中的许多将响应阿比特龙或第二代AR拮抗剂，但耐药性 不可避免地发展。这个阶段的一些患者可能对紫杉烷类或PARP抑制剂有反应，但 大多数患者都是有限的。Wnt信号的增加是其中一个机制， 对ASI耐药的影响经典的Wnt/β-catenin途径在Wnt配体结合时启动 卷曲家族受体，导致β-连环蛋白增加和TCF家族转录的共激活 因素Wnt的一个子集可以通过受体优先激活非经典Wnt途径，包括 ROR 1和ROR 2。下游信号通路不太明确，并且依赖于环境，但 包括平面细胞极性和Wnt-Ca++途径。值得注意的是，非经典的Wnt信号传导也已经被发现。 据报道抑制肿瘤抑制性Hippo通路，从而增强YAP 1的核表达， TAZ，随后刺激TEAD家族转录因子。Wnt 5a是主要的 非典型Wnt，其表达通常在癌症中失调，并且它与肿瘤- 抑制和促肿瘤活性。在PCa中，Wnt 5a表达增加与 mCRPC和神经内分泌PCa，但也与局部PCa的预后更好相关， 并具有生长抑制和休眠。虽然这些研究表明，非经典Wnt信号可以 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， 有待确定。我们已经发现Wnt 5a在PCa中的生长抑制作用是通过以下途径介导的： R 0 R2，并且该Wnt 5a/R 0 R2信号传导激活Hippo通路以抑制YAP 1/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并为Wnt 5a的生长抑制作用提供机制。我们假设 反映了ROR 2的一种新功能，该功能取决于环境，并且可以识别出能够识别的生物标志物 对Wnt 5a模拟药物如Foxy 5有反应的肿瘤亚群，Foxy 5目前在临床上用于治疗 审判该建议的中心假设是，驱动非经典Wnt的Wnt 5a模拟药物 信号传导可以是mCRPC（和其他实体瘤）子集的有效治疗， 抑制作用是通过Hippo途径激活，这反映了生理上的负面影响， 抑制YAP 1/TAZ活性的反馈回路。目的是确定Wnt 5a的分子基础。 介导的Hippo通路激活（目的1），并评估刺激这种激活的治疗潜力。 途径，包括鉴定可以预测哪些肿瘤可能对可用的 Wnt 5a-模拟药物（目的2）。