Targeting the Plk1/Pdcd4/mTORC2 Signaling to Treat Castration-Resistant Prostate Cancer

靶向 Plk1/Pdcd4/mTORC2 信号传导治疗去势抵抗性前列腺癌

• 批准号: 10731943
• 负责人: XIAOQI LIU
• 金额: $ 63.45万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-01 至 2028-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10731943
• 关键词: Ablation; Agreement; Androgen Receptor; Androgens; Apoptosis; Binding; Biochemical; Biometry; Cancer Patient; Castration; Cell Cycle; Cells; Chemoresistance; Clinical Research; Clinical Trials; Complex; Creativeness; Data; Development; Disease; Dominant-Negative Mutation; Down-Regulation; Drug resistance; Event; FRAP1 gene; Fostering; Genetically Engineered Mouse; Goals; Growth; Health; Human; Investigation; Knock-out; Laboratories; Malignant Neoplasms; Malignant neoplasm of prostate; Mission; Operative Surgical Procedures; Outcome; PLK1 gene; Pathology; Pathway interactions; Patient-Focused Outcomes; Patients; Peptides; Pharmaceutical Preparations; Phosphorylation; Play; Prostate Cancer therapy; Proteins; Public Health; Receptor Signaling; Regulation; Reporting; Repression; Research; Resistance; Role; Sampling; Signal Pathway; Signal Transduction; Specimen; System; Tertiary Protein Structure; Testing; Therapeutic; Tumor Suppression; Tumor Suppressor Proteins; United States National Institutes of Health; Work; Xenograft procedure; abiraterone; castration resistant prostate cancer; clinically significant; design; docetaxel; effective therapy; enzalutamide; genetic approach; improved; in vivo; inhibitor; innovation; mouse model; new therapeutic target; novel; novel strategies; patient derived xenograft model; programmed cell death protein 1; prostate cancer cell; prostate cancer progression; protein degradation; receptor expression; success; tumor growth; tumor initiation; tumor progression

Title: Targeting the Plk1/Pdcd4/mTORC2 signaling to treat castration-resistant prostate cancer Abstract Androgen receptor (AR) signaling is essential for development of prostate cancer (PCa), including castration- resistant prostate cancer (CRPC). Consequently, androgen signaling inhibitors (ASIs), such as abiraterone and enzalutamide, are becoming the first line treatment for CRPC. However, the limited success of ASIs makes it urgent to develop approaches to treat CRPC patients who are no longer responsive to ASIs. Programmed cell death 4 (Pdcd4) is a tumor suppressor, which has been demonstrated to inhibit tumor progression and chemoresistance. Furthermore, Pdcd4 is an androgen-repressed protein that regulates PCa growth and castration resistance. As such, it will be of clinical significance to understand the regulation mechanism of Pdcd4, as it will reveal novel approaches to overcome ASI resistance. Polo-like kinase 1 (Plk1), a critical regulator of cell cycle-related events, is a documented target for PCa treatment. Of note, we previously demonstrated that inhibition of Plk1 enhances the efficacy of ASIs. The long-term goals of this study are to identify druggable signaling pathways that offer effective treatment options for patients with CPRC who are no longer responsive to ASIs. The objective is to define the role of Plk1 in regulating Pdcd4 and to exploit these pathways as a novel therapeutic target for CRPC. Our data show that 1) Pdcd4 enhances the sensitivity to enzalutamide due to inhibition of mTORC2 (the mammalian target of rapamycin complex 2) and AR expression; 2) Plk1 phosphorylation of Pdcd4 results in its protein degradation; and 3) the dominant negative Pdcd4 peptide (TAT- RBD) overcomes ASI resistance in PCa. Based on these observations, we aim to test the central hypothesis that Plk1-associated phosphorylation of Pdcd4 results its degradation, which causes subsequent activation of the mTORC2, eventually contributing to activation of AR signaling and ASI resistance. Our hypothesis will be tested by pursuing three Specific Aims - (1) to demonstrate that loss of Pdcd4 to activate mTORC2 contributes to ASI resistance; (2) to dissect how Plk1 phosphorylation of Pdcd4 regulates its function as a tumor suppressor; and (3) to analyze clinical significance of Plk1 phosphorylation of Pdcd4. These complementary aims will be accomplished using biochemical analyses of signaling intermediates and employing genetic strategies with culture systems, inducible PCa mouse models, patient-derived xenograft (PDX) and human PCa samples. The rationale for the research is that it will probe the importance of Plk1-associated activity to Pdcd4 and to examine whether TAT-RBD peptide is a novel approach to treat ASI-resistant CRPC. This contribution is significant because, if positive, the results of the proposed study will support an immediate clinical trial for TAT-RBD peptide to treat CRPC that not respond to ASIs. The multiple-PI team, consisted of complementary expertise on Plk1 (X. Liu) and Pdcd4 (Yang), as well as prostate cancer pathology (Allison) and biostatistics (Chen), will be able to finish the proposed research in a timely manner.

标题：针对PLK1/PDCD4/MTORC2信号传导以治疗耐castration-Prostate Cancer 抽象的 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cast割 - 抗性前列腺癌（CRPC）。因此，雄激素信号抑制剂（ASI），例如阿比罗酮和 恩扎拉胺，正在成为CRPC的第一行治疗。但是，ASIS的成功有限 迫切需要开发治疗不再响应ASIS的CRPC患者的方法。编程单元格 死亡4（PDCD4）是肿瘤抑制剂，已证明可以抑制肿瘤进展和 化学抗性。此外，PDCD4是一种雄激素抑制的蛋白，可调节PCA生长和 cast割抵抗力。因此，了解PDCD4的调节机制，将具有临床意义。 由于它将揭示克服ASI抵抗的新方法。 polo样激酶1（PLK1），关键调节剂 与细胞周期相关的事件是PCA治疗的记录目标。值得注意的是，我们以前证明了 PLK1的抑制增强了ASIS的功效。这项研究的长期目标是确定可药的 为CPRC患者提供有效治疗选择的信号通路，他们不再有反应 到ASIS。目的是定义PLK1在调节PDCD4中的作用，并将这些途径作为一种新颖 CRPC的治疗靶标。我们的数据表明1）PDCD4提高了由于 MTORC2（雷帕霉素复合物2的哺乳动物靶标）和AR表达的抑制作用； 2）PLK1 PDCD4的磷酸化导致其蛋白质降解； 3）显性负PDCD4肽（tat- RBD）在PCA中克服了ASI抗性。基于这些观察，我们旨在检验中心假设 PDCD4的PLK1相关磷酸化导致其降解，这导致随后的激活 MTORC2，最终导致AR信号传导和ASI电阻的激活。我们的假设将进行检验 通过追求三个具体目标 - （1）证明PDCD4激活MTORC2的损失有助于ASI 反抗; （2）剖析PDCD4的PLK1磷酸化如何调节其作为肿瘤抑制剂的功能；和 （3）分析PDCD4的PLK1磷酸化的临床意义。这些补充目标将是 使用信号中间体的生化分析和采用遗传策略来完成 培养系统，可诱导的PCA小鼠模型，患者衍生的异种移植（PDX）和人PCA样品。这 这项研究的理由是，它将探究与PLK1相关活性对PDCD4的重要性并检查 TAT-RBD肽是否是治疗ASI耐药性CRPC的新方法。这项贡献很重要 因为，如果阳性，拟议的研究结果将支持TAT-RBD肽的立即临床试验 治疗不响应ASIS的CRPC。多个PI团队，包括PLK1的补充专业知识（X。 刘）和PDCD4（Yang）以及前列腺癌病理学（Allison）和生物统计学（Chen）将能够能够 及时完成拟议的研究。