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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

基本信息

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
项目类别：
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

项目摘要

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.

题目：靶向Plk1/Pdcd4/mTORC2信号治疗去势抵抗性前列腺癌