MAOA and AR Reciprocal Crosstalk in Prostate Cancer

MAOA 和 AR 在前列腺癌中的相互串扰

• 批准号: 10543753
• 负责人: Boyang Wu
• 金额: $ 34.3万
• 依托单位: WASHINGTON STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-01-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10543753
• 关键词: Acetates; Address; American; Androgen Antagonists; Androgen Receptor; Androgen Response Element; Androgens; Biochemical; Biological Assay; CYP17A1 gene; Cancer Etiology; Cancer Patient; Castration; Cessation of life; ChIP-seq; Chemicals; Clinical; Clinical Data; Clinical Management; Combined Modality Therapy; Complement; Complex; Coupled; Data Set; Dependence; Development; Disease; Disease Resistance; Drug resistance; E-Box Elements; Enhancers; Environment; Enzymes; Epigenetic Process; Evaluation; FDA approved; Foundations; Gene Expression; Gene set enrichment analysis; Genes; Genetic; Genetic Transcription; Genomics; Growth; Human; Hydrogen Peroxide; In Vitro; Incidence; Journals; Knowledge; Link; Malignant Neoplasms; Malignant neoplasm of prostate; Mediating; Mediator; Mitochondria; Molecular; Molecular Profiling; Molecular Target; Monoamine Oxidase A; NKX3-1 gene; Nature; Neoplasm Metastasis; New Agents; Oncogenic; Operative Surgical Procedures; Patients; Pharmaceutical Preparations; Prostate Cancer therapy; Reactive Oxygen Species; Receptor Signaling; Regulation; Reporting; Resistance; Resistance development; Role; Sampling; Signal Transduction; Surveys; System; TMPRSS2 gene; Testing; Tetracyclines; Transactivation; Translations; Treatment Protocols; Xenograft Model; abiraterone; advanced prostate cancer; androgen biosynthesis; androgen deprivation therapy; androgen sensitive; antagonist; cancer cell; cancer initiation; cancer prevention; castration resistant prostate cancer; clinical investigation; cohort; combat; dietary; effective therapy; efficacy evaluation; enzalutamide; improved; in vivo; inhibitor; innovation; insight; knock-down; mRNA Expression; men; molecular targeted therapies; monoamine; new combination therapies; next generation; novel; novel therapeutic intervention; pharmacologic; promoter; prostate cancer cell; prostate cancer cell line; prostate cancer progression; protein expression; response; small hairpin RNA; synergism; targeted treatment; therapeutic candidate; therapeutic target; transcription factor; transcriptome sequencing; treatment strategy; tumor; tumor growth; tumor progression

Project Summary/Abstract Prostate cancer (PC) is the most common non-skin cancer in American men, with a lifetime incidence of 1 in 7, and also the second leading cause of cancer death in American men. Androgen receptor (AR) is the primary oncogenic driver of PC growth, survival and progression. AR-directed therapy is currently the principal treatment regimen. Despite initial response rates exceeding 90%, PC eventually relapses and progresses to fatal castration-resistant PC (CRPC), where reactivation of AR signaling occurs in a low-androgen environment. Recent introduction of FDA-approved next-generation antiandrogens, including enzalutamide (ENZ) and abiraterone acetate (ABI), have improved the CRPC treatment landscape, but emergence of drug resistance remains nearly universal, with no AR-targeted therapeutic options afterwards. These dismal facts underscore the pressing clinical need to identify new molecular targets and develop effective therapies to combat advanced PC. Through integrated analysis of publicly available clinical PC data sets coupled with functional studies in AR-positive PC cells, we propose monoamine oxidase A (MAOA), which synergizes with AR to promote PC, as an ideal therapeutic candidate to complement AR-targeted therapy in CRPC. We identified a novel reciprocal interaction between MAOA and AR in PC cells. MAOA expression is induced by androgen treatment; and conversely, MAOA silencing significantly reduces AR activity by lowering AR target gene expression and responsiveness to androgen stimulation in PC cells under both androgen-replete and depleted conditions as well as in a CRPC xenograft model. We showed significant positive co-expression of MAOA and AR target genes (PSA, TMPRSS2, NKX3.1) in multiple clinical data sets, including CRPC. Importantly, we found MAOA genomic amplification and/or epigenetic activation in 64% of samples in a CRPC data set, reinforced by elevated MAOA protein expression in our CRPC patient cohort. Additionally, we demonstrated that inhibition of MAOA by genetic or pharmacological approaches enhanced the growth-inhibiting effects of ENZ and ABI in androgen-sensitive, CR and antiandrogen-resistant PC cells. Based on these findings, we will test the hypothesis that MAOA synergizes with AR through reciprocal crosstalk and convergent downstream signaling to amply MAOA/AR effects promoting AR-driven PC growth and progression, and that co-targeting MAOA/AR is an actionable, effective strategy to treat CRPC and reverse antiandrogen drug resistance. To address this hypothesis, three aims are proposed. In Aim 1, we will elucidate the mechanistic basis of MAOA- AR reciprocal interaction in PC cells. In Aim 2, we will characterize the role of MAOA in regulating the development and progression of CRPC in xenograft models. In Aim 3, we will determine the efficacy of MAOA inhibitors for treating CRPC and reversing resistance to next-generation antiandrogens in vitro and in vivo. These studies will provide fundamental innovative insights into AR regulation in CRPC and illuminate a path toward the development of new combination therapy for advanced PC.

项目概要/摘要 前列腺癌 (PC) 是美国男性中最常见的非皮肤癌，终生发病率为七分之一， 也是美国男性癌症死亡的第二大原因。雄激素受体（AR）是主要的 PC 生长、存活和进展的致癌驱动因素。 AR定向治疗是目前主要的治疗方法 治疗方案。尽管最初的缓解率超过 90%，但 PC 最终复发并进展为 致命的去势抵抗性 PC (CRPC)，其中 AR 信号重新激活发生在低雄激素环境中。 最近推出了 FDA 批准的下一代抗雄激素，包括恩杂鲁胺 (ENZ) 和 醋酸阿比特龙（ABI）改善了 CRPC 的治疗前景，但出现了耐药性 仍然几乎普遍存在，之后没有针对 AR 的治疗选择。这些令人沮丧的事实凸显 临床迫切需要确定新的分子靶点并开发有效的疗法来对抗 先进的电脑。通过对公开的临床 PC 数据集的综合分析以及功能 在 AR 阳性 PC 细胞的研究中，我们提出单胺氧化酶 A (MAOA)，它与 ​​AR 协同作用 推广 PC 作为 CRPC 中 AR 靶向治疗的理想治疗候选者。我们确定了一个 PC 细胞中 MAOA 和 AR 之间的新型相互作用。 MAOA 表达由雄激素诱导 治疗;相反，MAOA 沉默通过降低 AR 靶基因显着降低 AR 活性 雄激素充足和耗尽条件下 PC 细胞的表达和对雄激素刺激的反应 条件以及 CRPC 异种移植模型中。我们发现 MAOA 和 多个临床数据集中的 AR 靶基因（PSA、TMPRSS2、NKX3.1），包括 CRPC。重要的是，我们 在 CRPC 数据集中 64% 的样本中发现 MAOA 基因组扩增和/或表观遗传激活， 我们的 CRPC 患者队列中 MAOA 蛋白表达升高强化了这一点。此外，我们还展示了 通过遗传或药理学方法抑制 MAOA 增强了生长抑制作用 雄激素敏感、CR 和抗雄激素耐药 PC 细胞中的 ENZ 和 ABI。根据这些发现，我们将 检验 MAOA 通过相互串扰和下游收敛与 AR 协同作用的假设 信号传导可充分发挥 MAOA/AR 效应，促进 AR 驱动的 PC 生长和进展，并且共同靶向 MAOA/AR 是治疗 CRPC 和逆转抗雄激素耐药性的可行、有效的策略。到 针对这一假设，提出了三个目标。在目标 1 中，我们将阐明 MAOA-的机制基础 AR 在 PC 细胞中的相互作用。在目标 2 中，我们将描述 MAOA 在调节 异种移植模型中 CRPC 的发展和进展。在目标 3 中，我们将确定 MAOA 的功效 用于治疗 CRPC 并逆转体外和体内下一代抗雄激素耐药性的抑制剂。 这些研究将为 CRPC 中的 AR 调控提供基本的创新见解，并指明一条道路 致力于开发针对晚期 PC 的新联合疗法。