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：Plk 1作为前列腺癌的预后生物标志物 摘要 由于雄激素受体（AR）信号传导对于前列腺癌（PCa）的发展至关重要， 包括去势抵抗性前列腺癌（CRPC），雄激素信号抑制剂（ASI）， 成为CRPC的一线治疗药物。然而，ASI的有限临床成功使其 迫切需要开发新的方法来治疗ASI-CRPC。电离辐射是另一个主要的 治疗CRPC的方法疗效有限。奥拉帕尼是最近开发的一种PARP 1抑制剂， 用于靶向DNA修复缺陷的癌症，如BRCA突变。不幸的是， 奥拉帕尼在CRPC中的应用受到BRCA突变仅发生在低水平CRPC中的事实的严重限制。 PCa的百分比。因此，确定控制DNA损伤反应的其他关键调节因子， (DDR)因为它将识别对奥拉帕尼有反应的特定患者群体。 目的是确定polo样激酶1（Plk 1）在调节DDR中的作用，并利用其独特的 对奥拉帕尼治疗AS I耐药CRPC患者的疗效的影响。中心假设是Plk 1 Mre 11的磷酸化，MRN（Mre 11/Rad 50/Nbs 1）复合物的组分，和MDC 1（介导剂 DNA损伤检查点1），导致DNA损伤检查点过早终止，减少 DNA修复，因此基于合成致死性的概念增加了olabaparib的疗效。我们的数据 显示Plk 1直接磷酸化Mre 11，其激活是响应DNA的第一步 Mre 11的Plk 1磷酸化导致从DNA损伤检查点恢复， 减少DNA修复。我们还表明，MDC 1，一种进一步放大DDR信号的蛋白质，是Plk 1 衬底我们的假设将通过追求三个具体目标进行测试-（1）解剖Plk 1如何 Mre 11的磷酸化调节MRN复合物;（2）测试Mre 11的Plk 1磷酸化是否 MDC 1有助于检查点的过早终止;以及（3）确定Plk 1是否是一个 前列腺癌的预后生物标志物。这些互补的目标将利用生物化学 信号中间体的分析和采用细胞培养系统和遗传策略 诱导型小鼠模型。这项研究的基本原理是，它将探讨Plk 1的重要性， 并检查Plk 1是否可以作为奥拉帕尼在DDR中疗效的可预测生物标志物。 CRPC。这一贡献是重要的，因为如果是积极的，拟议的研究结果将支持 一项比较奥拉帕尼在携带不同水平CRPC患者中的疗效的即时临床试验 Plk 1的这项研究是创新的，因为它从一种新的Plk 1信号通路来研究这种疾病， 挑战了Plk 1仅用于调节有丝分裂事件的传统观点。这些研究 通过确定对DDR至关重要的关键调节因子，为治疗提供新的范例。 奥拉帕尼在CRPC中的疗效。