Plk1 as a prognostic biomarker for prostate cancer

Plk1 作为前列腺癌的预后生物标志物

基本信息

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
项目类别：
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

项目摘要

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 的临床成功有限使得它迫切需要开发新方法来治疗 ASI 耐药的 CRPC。电离辐射是另一个主要治疗 CRPC 的方法效果有限。奥拉帕尼 (Olaparib) 是一种 PARP1 抑制剂，最近被开发出来并用于靶向 DNA 修复缺陷的癌症，例如 BRCA 突变。不幸的是，使用奥拉帕尼在 CRPC 中的应用受到严重限制，因为 BRCA 突变仅发生在低水平人群中 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) 具有重要意义，因为它将确定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 (Plk1) 在调节 DDR 中的作用并利用其独特的奥拉帕尼对 ASI 耐药 CRPC 患者疗效的影响。中心假设是 Plk1 Mre11（MRN (Mre11/Rad50/Nbs1) 复合物的一个组成部分）和 MDC1（介质 DNA 损伤检查点 1)，导致 DNA 损伤检查点过早终止，减少 DNA 修复，从而基于合成致死的概念提高了olabparib 的功效。我们的数据表明 Plk1 直接磷酸化 Mre11，其激活是响应 DNA 的第一步 Mre11 的 Plk1 磷酸化可导致 DNA 损伤检查点恢复， DNA 修复减少。我们还表明，MDC1（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 如何 Mre11 的磷酸化调节 MRN 复合物； (2)检测Plk1是否磷酸化 MDC1 导致检查点过早终止； (3) 判断Plk1是否为 PCa 的预后生物标志物。这些互补的目标将通过生物化学来实现分析信号中间体并采用细胞培养系统和遗传策略与诱导小鼠模型。该研究的基本原理是探讨 Plk1 的重要性 DDR 并检查 Plk1 是否可以作为奥拉帕尼疗效的可预测生物标志物 CRPC。这一贡献意义重大，因为如果积极的话，拟议研究的结果将支持一项立即临床试验，比较奥拉帕尼对携带不同水平的 CRPC 患者的疗效 Plk1 的。这项研究具有创新性，因为它从一种新颖的 Plk1 信号通路来治疗疾病，挑战了 Plk1 仅发挥调节有丝分裂事件作用的传统观点。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。