Elucidating the Molecular Role of SYNCRIP in Prostate Cancer and AR Targeted Therapy Resistance

阐明 SYNCRIP 在前列腺癌和 AR 靶向治疗耐药中的分子作用

• 批准号: 10649422
• 负责人: Ping Mu
• 金额: $ 40.02万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-05-01 至 2026-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10649422
• 关键词: Affect; American; Apoptosis; Automobile Driving; Binding; Cancer Patient; Castration; Cell Proliferation; Cells; Clinical; Cytoplasm; DNA; DNA Sequence Alteration; Data; Deaminase; Dependence; Disease; Genes; Genetically Engineered Mouse; Genomics; Human; Impairment; In Vitro; Knock-out; Libraries; Malignant neoplasm of prostate; Mediating; Messenger RNA; Molecular; Mus; Mutagenesis; Mutate; Oncogenes; Oncogenic; Organoids; Outcome; Pathologic; Pathway interactions; Patient-Focused Outcomes; Patients; Pattern; Proteins; RNA-Protein Interaction; Reporting; Resistance; Resolution; Role; Signal Pathway; Tumor Suppressor Genes; Tumor Suppressor Proteins; Work; Xenograft Model; advanced prostate cancer; apoB mRNA editing catalytic subunit; cancer diagnosis; cancer initiation; castration resistant prostate cancer; enzalutamide; genetic testing; improved; in vitro Model; in vivo; insight; knock-down; men; mouse model; neoplastic cell; novel; prostate cancer cell; prostate cancer cell line; prostate cancer model; resistance mechanism; response; screening; senescence; synaptotagmin; targeted treatment; therapeutic development; therapeutic target; therapy resistant; treatment response; tumor; tumor growth; tumor heterogeneity; tumorigenesis

PROJECT SUMMARY Prostate cancer (PCa) is the most commonly diagnosed cancer among American men and metastatic Castration- Resistant Prostate Cancer (mCRPC) is the mostly deadly form of PCa. mCRPC is currently treated with AR targeted therapy, however resistance to the current therapies for mCRPC is unfortunately inevitable, underscoring the critical demand for elucidating the mechanisms of resistance and identifying actionable therapeutic targets to overcome resistance. We have identified the loss of Synaptotagmin Binding Cytoplasmic RNA Interacting Protein (SYNCRIP) as a top candidate conferring therapy resistance through a in vivo library screening examining genomic alterations which confer resistance. We discovered that the frequent deletion of SYNCRIP, occurring in approximately 14% of patients, is strongly associated with poor clinical outcomes of mCRPC patients receiving AR targeted therapy. Our data has demonstrated that depletion of SYNCRIP promotes resistance to AR targeted therapy both in vitro and in vivo. Mechanistically, we found significantly upregulated APOBEC-mediated DNA mutation patterns in both PCa cell lines and mCRPC patients with SYNCRIP depletion. The DNA deaminase APOBEC1, presumably sequestered by SYNCRIP, is required and sufficient for the AR targeted therapy resistance observed in SYNCRIP-depleted tumor cells. Thus, the overall objectives of this application are to define the molecular role of SYNCRIP in PCa tumorigenesis and AR targeted therapy resistance, and to elucidate the molecular mechanisms through which the loss of this protein promotes tumorigenesis and resistance, using human PCa cells, organoids, and mouse models. We proposed to elucidate the role of this putative tumor suppressor gene by testing the following central hypothesis: Loss of SYNCRIP confers resistance to AR targeted therapy through the ectopic APOBEC-mediated mutagenesis of key oncogenes and the activation of downstream signaling pathways. We will examine this hypothesis by pursuing three specific aims: In Aim 1, we will define whether SYNCRIP depletion promotes PCa tumorigenesis, including both primary PCa and mCRPC, and AR targeted therapy resistance using multiple human PCa cell lines, organoids, and xenograft models. We will also examine whether SYNCRIP depletion adjusts AR dependency and lineage plasticity. In Aim 2, we will elucidate the role of APOBEC-mediated mutagenesis in mediating AR targeted therapy resistance in cells with SYNCRIP depletion, and identify the mutated resistant driver genes. In Aim 3, we will determine the role of SYNCRIP in the initiation, progression, and response to AR targeted therapy of primary PCa using various mouse models. These proposed aims will capitalize on the expertise of our lab and of our collaborators to comprehensively define the role of SYNCRIP in PCa tumorigenesis and therapy resistance, and to elucidate the molecular mechanism through which the loss of this tumor suppressor confers resistance. The completion of this study will delineate novel insights into the mechanism of AR targeted therapy resistance and may identify new actionable therapeutic targets and approaches to overcome resistance, thus greatly improving the clinical outcome of patients with PCa.

项目摘要 前列腺癌（PCa）是美国男性中最常见的癌症， 耐药前列腺癌（mCRPC）是最致命的PCa形式。mCRPC目前接受AR治疗 靶向治疗，然而，不幸的是，对mCRPC当前治疗的耐药性是不可避免的， 强调迫切需要阐明耐药性机制， 治疗目标，以克服阻力。我们已经确定了突触结合蛋白结合细胞质的丢失， RNA相互作用蛋白（SYNCRIP）作为通过体内文库赋予治疗抗性的最佳候选物 筛选检查赋予抗性的基因组改变。我们发现，频繁删除 约14%的患者发生SYNCRIP，与以下不良临床结局密切相关： 接受AR靶向治疗的mCRPC患者。我们的数据表明SYNCRIP的消耗 在体外和体内促进对AR靶向疗法的抗性。从机制上讲，我们发现 PCa细胞系和mCRPC患者中APOBEC介导的DNA突变模式上调， SYNCRIP耗竭。DNA脱氨酶APOBEC1可能被SYNCRIP隔离， 足以应对在SYNCRIP缺失的肿瘤细胞中观察到的AR靶向治疗耐药性。因此， 本申请的目的是定义SYNCRIP在PCa肿瘤发生和AR靶向中的分子作用 治疗抗性，并阐明这种蛋白质的损失促进的分子机制 肿瘤发生和抗性，使用人PCa细胞、类器官和小鼠模型。我们建议澄清 通过检验以下中心假设来确定这种假定的肿瘤抑制基因的作用： 通过异位APOBEC介导的关键突变赋予对AR靶向治疗的抗性 癌基因和下游信号通路的激活。我们将通过以下方式检验这一假设： 追求三个具体目标：在目标1中，我们将确定SYNCRIP缺失是否促进PCa肿瘤发生， 包括原发性PCa和mCRPC，以及使用多种人PCa细胞的AR靶向治疗耐药性 细胞系、类器官和异种移植模型。我们还将研究SYNCRIP耗竭是否会调节AR 依赖性和谱系可塑性。在目标2中，我们将阐明APOBEC介导的诱变在以下方面的作用： 在SYNCRIP耗竭的细胞中介导AR靶向治疗抗性，并鉴定突变的抗性 驱动基因在目标3中，我们将确定SYNCRIP在AR的发生、进展和反应中的作用。 使用各种小鼠模型对原发性前列腺癌进行靶向治疗。这些拟议目标将利用 我们实验室和合作者的专业知识，全面定义SYNCRIP在PCa中的作用 肿瘤发生和治疗耐药性，并阐明通过这种损失的分子机制， 肿瘤抑制因子赋予抗性。这项研究的完成将描绘新的见解 AR靶向治疗耐药性的机制，并可能识别新的可操作的治疗靶点， 这是克服耐药性的方法，从而大大改善了PCa患者的临床结局。