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.

项目摘要/摘要 前列腺癌（PC）是美国男性最常见的非皮肤癌，生命周期的发病率为1中， 这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，生存和进展的致癌驱动力。 AR导向治疗目前是主要的 治疗方案。尽管初始答复率超过90％，但PC最终会复发并发展为 致命的castration耐药性PC（CRPC），其中AR信号的重新激活发生在低-----------环境中。 最近介绍了FDA批准的下一代抗dro仪，包括enzalutamide（ENZ）和 阿比罗酮乙酸盐（ABI）已改善了CRPC治疗景观，但耐药性的出现 仍然几乎普遍存在，此后没有针对AR的治疗选择。这些令人沮丧的事实强调了 紧迫的临床需求，以识别新的分子靶标并开发有效的疗法以对抗 高级PC。通过对公共可用临床PC数据集和功能的综合分析 在AR阳性PC细胞中的研究，我们提出了单胺氧化酶A（MAOA），该酶A（MAOA）与AR协同为 促进PC，是在CRPC中补充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表达是由雄激素诱导的 治疗;相反，MAOA沉默可以通过降低AR靶基因显着降低AR活性 在雄激素恢复和耗尽的情况下，PC细胞中PC细胞中雄激素刺激的表达和反应能力 条件以及CRPC异种移植模型。我们显示了MAOA和 包括CRPC在内的多个临床数据集中的AR靶基因（PSA，TMPRSS2，NKX3.1）。重要的是，我们 在CRPC数据集中，发现了64％的样品中的MAOA基因组扩增和/或表观遗传激活， 在我们的CRPC患者队列中的MAOA蛋白表达升高而增强。此外，我们证明了 通过遗传或药理方法抑制MAOA，增强了抑制生长的影响 ENZ和ABI对雄激素敏感，CR和抗雄激素的PC细胞。根据这些发现，我们将 测试MAOA通过相互串扰和下游收敛的AR协同的假设 向充分的MAOA/AR效应发出信号，促进AR驱动PC的生长和进展，并进行靶向 MAOA/AR是治疗CRPC和反向抗二氧化碳药物耐药性的可行，有效的策略。到 解决了这一假设，提出了三个目标。在AIM 1中，我们将阐明MAOA-的机械基础 PC细胞中的AR相互作用。在AIM 2中，我们将表征MAOA在调节的角色 异种移植模型中CRPC的发展和进展。在AIM 3中，我们将确定MAOA的功效 用于治疗CRPC和逆转对下一代抗雄激素的耐药性的抑制剂。 这些研究将为CRPC中的AR调节提供基本的创新见解，并阐明一条路径 为了开发高级PC的新组合疗法。