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: 8932479
• 负责人: Jindan Yu
• 金额: $ 28.07万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-08-18 至 2020-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8932479
• 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 Neoplasms; 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; Relative (related person); Reporting; Residual state; Resistance; Resistance development; Role; Signal Transduction; Specimen; Staging; Staining method; Stains; TGF-beta type I receptor; Testing; Therapeutic; Time; Tissue Microarray; Tissues; Transforming Growth Factor beta; Tumor Cell Invasion; Work; Xenograft procedure; castration resistant prostate cancer; cell growth; cell motility; cofactor; combinatorial; deprivation; feeding; improved; in vivo; in vivo Model; inhibitor/antagonist; loss of function mutation; men; novel strategies; novel therapeutic intervention; novel therapeutics; overexpression; phase 1 study; phase I trial; preclinical study; prostate cancer cell; research study; response; slug; success; targeted treatment; tumor; tumor growth; tumor xenograft; tumorigenic

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）是美国男性最常见的非皮肤癌。雄激素剥夺 靶向雄激素受体（AR）的疗法（ADT）是转移性PC的主要治疗方法。新的- 一代抗雄激素enzalutamide（ENZ）在延长患者寿命将近整整一年方面有效 然而抵抗力迅速发展。重要的是，castration抗性PC（CRPC）主要由异常驱动 低雄激素环境中AR的激活。 AR主要通过基因组发挥其致瘤作用 靶基因表达的调节。这种基因组作用受许多辅助因子的严格调节，其中之一 这是foxa1。传统上，FOXA1在雄激素刺激的AR信号传导中被称为AR共激活因子。 但是，生物标志物研究报告了有关FOXA1的有争议的结果 结果预测因子，表明背景或依赖治疗的角色。此外，经常性，功能丧失 在PC中发现了FOXA1的突变，表明肿瘤抑制作用。我们最近发现，虽然 相对于良性组织，FOXA1在局部PC中略有上调，它在 CRPC。机械研究表明，FOXA1在其对AR信号传导的调节中具有双重作用。在场 雄激素，FOXA1增强了AR信号传导并诱导细胞生长。但是，在没有雄激素的情况下 FOXA1抑制残留的AR活性，因此FOXA1损失导致与雄激素无关的AR激活 和耐castration的PC细胞生长。此外，我们发现FOXA1损失也打开了TGF /slug途径 有助于细胞迁移和侵袭。此外，在耐ENZ的CRPC中也激活了TGF /SLUG途径 细胞。因此，我们假设靶向TGF /SLUG信号的临床上可用的ALK5抑制剂可能会抑制 CRPC的进展并克服组合疗法中的ENZ抗性。为了检验这一假设，三个 提出了具体目标。在AIM 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。 AIM 2将表征下游途径 CRPC细胞和PC标本中的FOXA1。在AIM 3中，我们将研究ENZ的功效与 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 组合ENZ和ALK5抑制剂的转移性CRPC治疗。对于目标1和2，我们提出初步 数据，但在不是耐Castrate抗性的LNCAP细胞中；我们尚未在CRPC细胞系中检验我们的假设， 这与该提案更相关。此外，AIM 1和 AIM 2中的IHC染色涉及大量工作，并且尚未进行。此外，实际上 目标3和4中的所有拟议工作尚未完成。孢子资金对我们进行这项工作至关重要 项目。