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：项目概要 前列腺癌（PC）是美国男性中最常见的非皮肤癌。雄激素剥夺 靶向雄激素受体（AR）的ADT疗法是转移性PC的主要治疗方法。新- 第二代抗雄激素Enzalutamide（Enz）可有效延长患者生命近一整年 然而耐药性却迅速发展。重要的是，去势抵抗性PC（CRPC）主要由异常的 在低雄激素环境中激活AR。AR主要通过基因组途径发挥其致瘤作用， 调节靶基因表达。这种基因组作用受到许多辅因子的严格调控，其中一种辅因子是 也就是FOXA 1 FOXA 1传统上被认为是雄激素刺激的AR信号传导中的AR共激活剂。 然而，生物标志物研究报告了关于FOXA 1阳性或阴性的有争议的结果。 结果预测因子，提示背景或治疗依赖性作用。此外，复发性功能丧失 在PC中发现FOXA 1的突变，表明其具有肿瘤抑制作用。我们最近发现，尽管 相对于良性组织，FOXA 1在局限性PC中略微上调，在非局限性PC中显著下调。 CRPC。机制研究表明，FOXA 1在AR信号转导中具有双重作用。存在下 FOXA 1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， FOXA 1抑制残余AR活性，因此FOXA 1缺失导致雄激素非依赖性AR激活 和抗去势PC细胞生长。此外，我们发现FOXA 1的缺失也开启了TGF /slug通路， 有助于细胞迁移和侵入。此外，TGF /slug通路也在耐酶CRPC中被激活 细胞因此，我们假设，临床上可获得的靶向TGF /slug信号传导的ALK 5抑制剂可能抑制TGF /slug信号传导。 CRPC进展和克服联合治疗中的Enz-resistance。为了验证这一假设， 提出了具体目标。在目标1中，我们将阐明FOXA 1在抑制CRPC进展中的作用， 体外和最重要的是在体内异种移植肿瘤中。目标2将描述 CRPC细胞和PC标本中的FOXA 1。在目标3中，我们将研究Enz联合 ALK 5抑制剂在CRPC细胞系和异种移植物中的应用，而Aim 4将开发一项I期临床试验， 转移性CRPC的Enz和ALK 5抑制剂的组合治疗。对于目标1和2，我们提出了初步的 数据，但在非去势抵抗的LNCaP细胞中;我们尚未在CRPC细胞系中检验我们的假设， 这与这个提议更相关。此外，在目标1和目标2中描述的拟议动物实验也是可行的。 目标2中的IHC染色涉及大量工作，尚未进行。此外，几乎 目标3和4中提议的所有工作都尚未完成。SPORE资金对我们实现这一目标至关重要 项目