Plk1 as a prognostic biomarker for prostate cancer

Plk1 作为前列腺癌的预后生物标志物

• 批准号: 10306968
• 负责人: XIAOQI LIU
• 金额: $ 54.8万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-01 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10306968
• 关键词: Affect; Androgen Receptor; Androgens; BRCA mutations; Biochemical; Cancer Patient; Castration; Cell Culture System; Cells; Chromatin; Clinic; Clinical; Clinical Research; Clinical Trials; Complex; DNA Damage; DNA Repair; DNA Repair Gene; DNA Repair Pathway; DNA amplification; DNA damage checkpoint; Data; Defect; Development; Disease; Event; Exhibits; Fostering; Frequencies; Genetically Engineered Mouse; Goals; Health; Investigation; Ionizing radiation; Malignant Neoplasms; Malignant neoplasm of prostate; Mediator of activation protein; Meiotic Recombination; Mission; Mitotic; Mus; Mutation; Outcome; PLK1 gene; Patient-Focused Outcomes; Patients; Phosphorylation; Phosphotransferases; Poly(ADP-ribose) Polymerases; Prognostic Marker; Proteins; Public Health; Receptor Signaling; Recovery; Research; Resistance; Role; Sampling; Signal Pathway; Signal Transduction; Testing; Therapeutic; Tumor Subtype; Withdrawal; Work; abiraterone; ataxia telangiectasia mutated protein; base; brca gene; cancer cell; castration resistant prostate cancer; clinically relevant; comparative efficacy; cytotoxic; design; efficacy evaluation; genetic approach; improved; inhibitor/antagonist; innovation; mouse model; novel; novel strategies; overexpression; patient population; predictive marker; premature; prostate cancer cell; prostate cancer progression; response; success; tumor

Title: Plk1 as a prognostic biomarker for prostate cancer Abstract Because androgen receptor (AR) signaling is essential for development of prostate cancer (PCa), including castration-resistant prostate cancer (CRPC), androgen signaling inhibitors (ASI) are becoming the first line treatment for CRPC. However, the limited clinical success of ASIs makes it urgent to develop new approaches to treat ASI-resistant CRPC. Ionizing radiation is another major approach to treat CRPC with limited efficacy. Olaparib, a PARP1 inhibitor, is recently developed and used to target cancers with a defect in DNA repair, such as BRCA mutations. Unfortunately, the usage of olaparib in CRPC is profoundly limited by the fact that BRCA mutations only occur in low percentages of PCa. Thus, identifying additional critical regulators that control DNA damage response (DDR) is of significance as it will identify specific patient populations who will be responsive to olaparib. The objective is to define the role of polo-like kinase 1 (Plk1) in regulating DDR and to exploit its unique impact on the efficacy of olaparib for ASI-resistant CRPC patients. The central hypothesis is that Plk1 phosphorylation of Mre11, a component of MRN (Mre11/Rad50/Nbs1) complex, and MDC1 (mediator of DNA damage checkpoint 1), leads to premature termination of DNA damage checkpoint, reduced DNA repair, thus increased olabparib efficacy based on the concept of synthetic lethality. Our data show that Plk1 directly phosphorylates Mre11, whose activation is the first step in response to DNA damage and that Plk1 phosphorylation of Mre11 leads to recovery from DNA damage checkpoint and reduced DNA repair. We also show that MDC1, a protein that further amplifies DDR signals, is a Plk1 substrate. Our hypothesis will be tested by pursuing three Specific Aims - (1) to dissect how Plk1 phosphorylation of Mre11 regulates the MRN complex; (2) to test whether Plk1 phosphorylation of MDC1 contributes to premature termination of checkpoint; and (3) to determine whether Plk1 is a prognostic biomarker for PCa. These complementary aims will be accomplished using biochemical analyses of signaling intermediates and employing both cell culture systems and genetic strategies with inducible mouse models. The rationale for the research is that it will probe the importance of Plk1 to DDR and to examine whether Plk1 can be a predictable biomarker for the efficacy of olaparib in CRPC. This contribution is significant because, if positive, the results of the proposed study will support an immediate clinical trial to compare the efficacy of olaparib in CRPC patients carrying different levels of Plk1. The research is innovative as it approaches the disease from a novel Plk1 signaling pathway, challenging the traditional view that Plk1 functions solely to regulate mitotic events. These studies provide a new paradigm for therapies by identifying the key regulator of DDR that is critical for the efficacy of olaparib in CRPC.

标题：PLK1作为前列腺癌的预后生物标志物 抽象的 因为雄激素受体（AR）信号传导对于前列腺癌（PCA）的发展至关重要，所以 包括cast割的前列腺癌（CRPC），雄激素信号抑制剂（ASI）为 成为CRPC的第一行治疗。但是，ASIS的临床成功有限 迫切需要开发新方法来治疗ASI耐药性CRPC。电离辐射是另一个主要的 用有限的疗效治疗CRPC的方法。 Olaparib是PARP1抑制剂，最近开发了 用于靶向具有DNA修复缺陷的癌症，例如BRCA突变。不幸的是，用法 CRPC中Olaparib的of受到BRCA突变仅出现在低点的事实受到了极大的限制。 PCA的百分比。因此，确定控制DNA损伤响应的其他关键调节器 （DDR）具有重要意义，因为它将确定对Olaparib有反应的特定患者人群。 目的是定义类似马球的激酶1（PLK1）在调节DDR中的作用并利用其独特的作用 对Olaparib对ASI耐药性CRPC患者的疗效的影响。中心假设是PLK1 MRE11的磷酸化，MRN（MRE11/RAD50/NBS1）复合物和MDC1的成分（介体） DNA损伤检查点1），导致DNA损伤检查点过早终止，减少 DNA修复，从而根据合成致死性的概念提高了奥拉伯果的功效。我们的数据 证明PLK1直接磷酸化MRE11，其激活是对DNA的第一步 损坏和MRE11的PLK1磷酸化导致从DNA损伤检查点恢复 DNA修复减少。我们还表明，MDC1是一种进一步放大DDR信号的蛋白质，是PLK1 基材。我们的假设将通过追求三个具体目标来检验 - （1）剖析PLK1的方式 MRE11的磷酸化调节MRN复合物； （2）测试PLK1是否磷酸化 MDC1有助于过早终止检查点； （3）确定PLK1是否是 PCA的预后生物标志物。这些补充目标将使用生化实现 信号中间体和采用细胞培养系统和遗传策略的分析 使用诱导小鼠模型。该研究的理由是它将探究PLK1的重要性 DDR并检查PLK1是否可以成为Olaparib疗效的可预测的生物标志物 CRPC。这项贡献很重要，因为如果肯定，则提议的研究结果将支持 立即进行临床试验，以比较Olaparib在具有不同水平的CRPC患者中的功效 PLK1。这项研究具有创新性，因为它从新型的PLK1信号通路接近该疾病时， 挑战传统观点，即PLK1仅起作用以调节有丝分裂事件。这些研究 通过识别DDR的关键调节剂，为疗法提供新的范式 Olaparib在CRPC中的功效。