MAOA and AR Reciprocal Crosstalk in Prostate Cancer

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1/7， 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导向治疗是目前主要的 治疗方案。尽管最初的反应率超过90%，PC最终复发并进展到 致死性去势抵抗性PC（CRPC），其中AR信号转导的再激活发生在低雄激素环境中。 最近引入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，没有AR靶向治疗选择之后。这些令人沮丧的事实强调， 迫切的临床需求，以确定新的分子靶点，并开发有效的治疗方法，以打击 先进的PC通过对公开可用的临床PC数据集的综合分析， 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， 促进PC，作为补充CRPC中AR靶向治疗的理想治疗候选药物。我们确定了一个 PC细胞中MAOA和AR之间的新的相互作用。雄激素诱导MAOA表达 相反，MAOA沉默通过降低AR靶基因的表达而显著降低AR活性。 PC细胞在雄激素充足和缺乏条件下的表达和对雄激素刺激的反应性 条件以及CRPC异种移植模型中。我们显示MAOA和MAOA显着阳性共表达 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64%的样本中发现MAOA基因组扩增和/或表观遗传激活， 在我们的CRPC患者队列中，MAOA蛋白表达升高加强了这一点。此外，我们还证明了 通过遗传或药理学方法抑制MAOA增强了 雄激素敏感、CR和抗雄激素抗性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会聚与AR协同作用的假设 信号转导充分发挥MAOA/AR作用，促进AR驱动的PC生长和进展， MAOA/AR是治疗CRPC和逆转抗雄激素药物耐药性的可行、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- PC细胞中的AR相互作用。在目标2中，我们将描述MAOA在调节 CRPC在异种移植模型中的发展和进展。在目标3中，我们将确定MAOA的疗效 用于治疗CRPC和在体外和体内逆转对下一代抗雄激素的抗性的抑制剂。 这些研究将为CRPC的AR调控提供基本的创新见解，并为CRPC的AR调控提供一条新的途径。 为晚期PC开发新的联合疗法。

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.