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：靶向Plk1/Pdcd4/mTORC2信号通路治疗去势抵抗前列腺癌 摘要 雄激素受体(AR)信号在前列腺癌(PCa)的发生发展中是必不可少的，包括去势- 耐药前列腺癌(CRPC)。因此，雄激素信号转导抑制物(ASI)，如阿比特龙和 苯扎鲁胺正成为CRPC的一线治疗药物。然而，ASIS的有限成功使其 迫切需要开发治疗对ASIS不再有反应的CRPC患者的方法。程控单元 Death 4(Pdcd4)是一种肿瘤抑制因子，已被证明可以抑制肿瘤的进展和 化疗耐药。此外，Pdcd4是一种雄激素抑制蛋白，调节前列腺癌的生长和 抵抗阉割。因此，了解Pdcd4的调控机制具有重要的临床意义。 因为它将揭示克服ASI耐药性的新方法。Polo-like kinase1(Plk1)，一种关键的蛋白调节因子 细胞周期相关事件，是有文献记载的PCA治疗的靶点。值得注意的是，我们之前已经证明了 抑制Plk1可增强ASIS的疗效。这项研究的长期目标是确定可用药 为不再有反应的CPRC患者提供有效治疗选择的信号通路 致阿希斯。目的是确定Plk1在调节Pdcd4中的作用，并将这些途径作为一种新的 CRPC的治疗靶点。我们的数据显示，1)Pdcd4增强了对苯扎鲁胺的敏感性，这是由于 抑制mTORC2(雷帕霉素复合体2的哺乳动物靶点)和AR的表达；2)Plk1 Pdcd4的磷酸化导致其蛋白质降解；以及3)主要的负性Pdcd4肽(Tat- RBD)克服了PCA对ASI的抗性。基于这些观察，我们的目标是检验中心假设 PLK1相关的Pdcd4的磷酸化导致其降解，从而导致随后的激活 MTORC2，最终参与AR信号的激活和ASI的抵抗。我们的假设将得到检验 通过追求三个具体目标-(1)证明Pdcd4的丢失激活mTORC2有助于ASI (2)分析Pdcd4的Plk1磷酸化如何调节其作为肿瘤抑制因子的功能；以及 (3)分析Pdcd4蛋白Plk1磷酸化的临床意义。这些互补的目标将是 使用信号中间产物的生化分析，并使用遗传策略 培养系统、可诱导的PCA小鼠模型、患者来源的异种移植(PDX)和人类PCA样本。这个 这项研究的基本原理是，它将探索Plk1相关活动对Pdcd4的重要性，并检查 TAT-RBD多肽是否是治疗ASI耐药CRPC的新途径。这一贡献是巨大的 因为，如果呈阳性，拟议的研究结果将支持立即对TAT-RBD多肽进行临床试验 治疗对ASIS无效的CRPC。多PI团队由Plk1(X. 刘)和Pdcd4(杨)，以及前列腺癌病理学(Allison)和生物统计学(Chen)，将能够 及时完成拟议的研究工作。