Targeting FOXA1-downstream pathways: a novel therapeutic strategy for castration-resistant prostate cancer

靶向 FOXA1 下游通路：去势抵抗性前列腺癌的新型治疗策略

• 批准号: 9752248
• 负责人: Jindan Yu
• 金额: $ 27.39万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至 2021-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9752248
• 关键词: Adult; American; Androgen Antagonists; Androgen Receptor; Androgens; Animal Experiments; Benign; Biological Markers; Cancer Cell Growth; Cancer Etiology; Cancer Patient; Castration; Cell Line; Cells; Cessation of life; Clinical; DNA-Binding Proteins; Data; Development; Diagnosis; Disease; Epithelial; Family; Funding; Gene Expression; Generations; Genes; Genomics; Human; Hyperplasia; Immunohistochemistry; In Vitro; Kinetics; Knock-out; LNCaP; Life; Malignant neoplasm of prostate; Maximum Tolerated Dose; Metastatic Prostate Cancer; Monitor; Mus; Neoplasm Metastasis; Outcome; Pathway interactions; Patients; Phase I Clinical Trials; Pre-Clinical Model; Prostate; Receptor Activation; Receptor Signaling; Recurrence; Regulation; Reporting; Residual state; Resistance; Resistance development; Role; Signal Transduction; Specimen; Stains; TGF-beta type I receptor; Testing; Time; Tissue Microarray; Tissues; Transforming Growth Factor beta; Work; Xenograft procedure; androgen deprivation therapy; castration resistant prostate cancer; cell growth; cell motility; cofactor; combinatorial; experimental study; improved; in vivo; in vivo Model; inhibitor/antagonist; knock-down; loss of function mutation; men; novel strategies; novel therapeutic intervention; novel therapeutics; outcome prediction; overexpression; phase 1 study; phase I trial; preclinical study; primary endpoint; prostate cancer cell; slug; success; targeted treatment; treatment response; tumor; tumor growth; tumor xenograft; tumorigenic; virtual

PROJECT 4: PROJECT SUMMARY Prostate cancer (PC) is the most commonly diagnosed non-skin cancer in American men. Androgen deprivation therapies (ADT) that target the androgen receptor (AR) are the mainstay treatment for metastatic PC. New- generation anti-androgen enzalutamide (Enz) has been effective in prolonging patient life for almost a full year and yet resistance develops rapidly. Importantly, castration-resistant PC (CRPC) is driven primarily by aberrant activation of the AR in the milieu of low androgen. The AR exerts its tumorigenic roles mainly through genomic regulation of target gene expression. This genomic action is tightly regulated by a number of cofactors, one of which is FOXA1. FOXA1 is traditionally known as an AR co-activator in androgen-stimulated AR signaling. However, biomarker studies have reported controversial results regarding FOXA1 as a positive or negative outcome predictor, suggesting context- or treatment-dependent roles. In addition, recurrent, loss-of-function mutations of FOXA1 have been found in PC indicating tumor suppressive roles. We recently found that although FOXA1 is slightly up-regulated in localized PC relative to benign tissues, it is dramatically down-regulated in CRPC. Mechanistic studies revealed that FOXA1 has dual roles in its regulation of AR signaling. In the presence of androgen, FOXA1 enhances AR signaling and induces cell growth. However, in the absence of androgen, FOXA1 suppresses residual AR activity and as such FOXA1 loss leads to androgen-independent AR activation and castration-resistant PC cell growth. Moreover, we found that FOXA1 loss also turns on TGF /slug pathway contributing to cell migration and invasion. Further, TGF /slug pathway is also activated in Enz-resistant CRPC cells. We thus hypothesize that clinically-available ALK5 inhibitors that target TGF /slug signaling may suppress CRPC progression and overcome Enz-resistance in combinatorial therapies. To test this hypothesis, three specific aims are proposed. In Aim 1 we will elucidate the roles of FOXA1 in suppressing CRPC progression in vitro and most importantly in xenograft tumors in vivo. Aim 2 will characterize the downstream pathways of FOXA1 in CRPC cells and PC specimens. In Aim 3 we will investigate the efficacy of Enz in combination with ALK5 inhibitor in CRPC cell lines and xenografts, whereas Aim 4 will develop a phase I clinical trial of combinatorial Enz and ALK5 inhibitor treatment of metastatic CRPC. For Aims 1 and 2, we present preliminary data, but in LNCaP cells that are not castrate resistant; we have yet to test our hypothesis in CRPC cell lines, which are more relevant to this proposal. In addition, the proposed animal experiments described in Aim 1 and IHC staining in Aim 2 involve a substantial amount work and have not yet been performed. Furthermore, virtually all of the proposed work in Aims 3 and 4 is yet to be done. SPORE funding is critical for us to carry out this project.

项目 4：项目摘要 前列腺癌（PC）是美国男性中最常诊断出的非皮肤癌。雄激素剥夺 针对雄激素受体 (AR) 的疗法 (ADT) 是转移性 PC 的主要治疗方法。新的- 第一代抗雄激素恩杂鲁胺 (Enz) 已有效延长患者生命近一整年 然而阻力却在迅速发展。重要的是，去势抵抗性 PC (CRPC) 主要是由异常驱动的 在低雄激素环境下激活 AR。 AR主要通过基因组发挥其致瘤作用 靶基因表达的调控。这种基因组作用受到许多辅助因子的严格调节，其中之一 这是FOXA1。 FOXA1 传统上被称为雄激素刺激的 AR 信号传导中的 AR 共激活剂。 然而，生物标志物研究报告了有关 FOXA1 阳性或阴性的争议结果 结果预测因子，表明依赖于环境或治疗的作用。此外，复发性功能丧失 在 PC 中发现了 FOXA1 突变，表明具有肿瘤抑制作用。我们最近发现，虽然 相对于良性组织，FOXA1 在局部 PC 中略微上调，在 CRPC。机制研究表明 FOXA1 在 AR 信号传导调节中具有双重作用。在场的情况下 雄激素的 FOXA1 增强 AR 信号传导并诱导细胞生长。然而，在缺乏雄激素的情况下， FOXA1 抑制残余 AR 活性，因此 FOXA1 缺失导致不依赖雄激素的 AR 激活 和去势抵抗性 PC 细胞生长。此外，我们发现 FOXA1 丢失也会开启 TGF/slug 通路 有助于细胞迁移和侵袭。此外，TGF/slug 通路在 Enz 抗性 CRPC 中也被激活 细胞。因此，我们假设临床上可用的针对 TGF/slug 信号传导的 ALK5 抑制剂可能会抑制 CRPC 进展并克服组合疗法中的 Enz 耐药性。为了检验这个假设，三个 提出了具体目标。在目标 1 中，我们将阐明 FOXA1 在抑制 CRPC 进展中的作用 体外，最重要的是体内异种移植肿瘤。目标 2 将描述下游途径 CRPC 细胞和 PC 标本中的 FOXA1。在目标 3 中，我们将研究 Enz 与 CRPC 细胞系和异种移植物中的 ALK5 抑制剂，而 Aim 4 将开发 I 期临床试验 Enz 和 ALK5 抑制剂组合治疗转移性 CRPC。对于目标 1 和 2，我们提出初步的 数据，但在不具有去势抵抗性的 LNCaP 细胞中；我们尚未在 CRPC 细胞系中检验我们的假设， 哪些内容与本提案更相关。此外，目标 1 和中描述的拟议动物实验 Aim 2 中的 IHC 染色涉及大量工作，但尚未进行。此外，实际上 目标 3 和 4 中拟议的所有工作尚未完成。 SPORE 资金对于我们实现这一目标至关重要 项目。