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 信号传导治疗去势抵抗性前列腺癌 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，包括去势- 耐药性前列腺癌（CRPC）。因此，雄激素信号抑制剂（ASI），如阿比特龙和 enzalutamide 正在成为 CRPC 的一线治疗药物。然而，ASI 的成功有限，使得 迫切需要开发方法来治疗对 ASI 不再有反应的 CRPC 患者。程序化细胞 死亡 4 (Pdcd4) 是一种肿瘤抑制因子，已被证明可以抑制肿瘤进展并 化学耐药性。此外，Pdcd4 是一种雄激素抑制蛋白，可调节 PCa 生长和 去势抵抗。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 阻力的新方法。 Polo 样激酶 1 (Plk1)，一个重要的调节因子 细胞周期相关事件是 PCa 治疗的记录目标。值得注意的是，我们之前证明了 抑制 Plk1 可增强 ASI 的功效。这项研究的长期目标是确定可成药的药物 信号通路为不再有反应的 CPRC 患者提供有效的治疗选择 到 ASI。目的是确定 Plk1 在调节 Pdcd4 中的作用，并利用这些途径作为一种新的途径 CRPC 的治疗靶点。我们的数据表明 1) Pdcd4 增强了对恩杂鲁胺的敏感性，因为 抑制 mTORC2（雷帕霉素复合物 2 的哺乳动物靶标）和 AR 表达； 2）PLK1 Pdcd4 的磷酸化导致其蛋白质降解； 3) 显性失活 Pdcd4 肽 (TAT- RBD）克服了 PCa 中的 ASI 抵抗。基于这些观察，我们的目标是检验中心假设： Plk1 相关的 Pdcd4 磷酸化导致其降解，从而导致随后激活 mTORC2，最终有助于激活 AR 信号传导和 ASI 抵抗。我们的假设将得到检验 通过追求三个具体目标 - (1) 证明失去 Pdcd4 来激活 mTORC2 有助于 ASI 反抗; (2) 剖析Plk1磷酸化Pdcd4如何调节其抑癌功能；和 (3)分析Plk1磷酸化Pdcd4的临床意义。这些互补的目标将是 通过对信号中间体进行生化分析并采用遗传策略来完成 培养系统、诱导型 PCa 小鼠模型、患者来源的异种移植物 (PDX) 和人类 PCa 样本。这 该研究的基本原理是它将探讨 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。这个贡献意义重大 因为，如果呈阳性，拟议研究的结果将支持立即进行 TAT-RBD 肽的临床试验 治疗对 ASI 无反应的 CRPC。多 PI 团队由 Plk1 (X. Liu）和 Pdcd4（Yang），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。