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Improving chemotherapy of castration-resistant prostate cancer.

改善去势抵抗性前列腺癌的化疗。

基本信息

批准号：
10316730
负责人：
XIAOQI LIU
金额：
$ 34.65万
依托单位：
UNIVERSITY OF KENTUCKY
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-08-10 至 2026-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10316730
关键词：
Ablation Affect Androgen Receptor Androgens Binding Biochemical Bromodomain Castration Cell Cycle Cell Cycle Progression Cell Proliferation Cells Chemoresistance Chromatin Clinical Research Data Development Disease Docking Epigenetic Process Event Family Fostering Genetic Transcription Genetically Engineered Mouse Goals Growth and Development function Health Investigation Lead Lysine Malignant Neoplasms Malignant neoplasm of prostate Methodology Mission Mitosis Mitotic Molecular Mutation Operative Surgical Procedures Outcome PLK1 gene Paclitaxel Patient-Focused Outcomes Patients Pharmaceutical Preparations Phosphorylation Phosphorylation Site Phosphotransferases Proteins Public Health Reader Receptor Signaling Regulation Research Resistance Resistance development Role Signal Pathway Signal Transduction Site Specimen System Testing Therapeutic Therapeutic Agents Transcriptional Elongation Factors United States National Institutes of Health Work Xenograft procedure abiraterone castration resistant prostate cancer chemotherapy clinically significant cyclin T1 design docetaxel effective therapy genetic approach genomic locus improved in vivo inhibitor/antagonist innovation loss of function mutation member mouse model multicatalytic endopeptidase complex novel novel strategies patient derived xenograft model prostate cancer cell prostate cancer progression protein degradation recruit standard care success therapy resistant ubiquitin-protein ligase

项目摘要

Title: Improving chemotherapy of castration-resistant prostate cancer Abstract Androgen receptor (AR) signaling is essential for prostate cancer (PCa) development and growth, even in castration-resistant PCa (CRPC), the lethal stage of the disease. Docetaxel is the standard treatment for CRPC patients due to a combination of mitotic catastrophe and inhibition of AR signaling. Androgen signaling inhibitors (ASI) are also used to treat CRPC post-docetaxel with limited success. Therefore, it is urgent to identify new targets and develop novel approaches to treat CRPC that are resistant to the existing therapies. Brd4, a conserved member of the bromodomain and extraterminal (BET) family of chromatin readers, promotes gene transcription via interacting with core positive transcription elongation factor (P-TEFb), consisting of Cdk9 and cyclin T1. Significantly, AR signaling-competent CRPC cells are preferentially sensitive to Brd4 inhibitor JQ1 as JQ1 treatment disrupts AR recruitment to target gene loci, thus resulting in inhibition of AR signaling directly. Furthermore, JQ1 enhances the efficacy of ASI in PCa. Loss-of-function mutations in E3 ubiquitin ligase substrate-binding adaptor speckle-type POZ protein (SPOP) cause stabilization of Brd4 and JQ1 resistance. Thus, it will be of clinical significance to understand the regulation mechanism of Brd4 regulation and to develop a new approach to cause Brd4 degradation even in the presence of SPOP mutations. The long-term goals of this study are to identify novel and druggable signaling pathways that offer more effective treatment options for patients with therapy-resistant CRPC. The objective is to define the role of polo-like kinase 1 (Plk1) in regulating Brd4 degradation and AR signaling, and to exploit this unique mechanism to develop a novel approach for treatment. Our preliminary data show that Plk1 phosphorylation of Brd4 leads to its protein degradation even in the presence of SPOP mutations. The central hypothesis is that Plk1-associated phosphorylation of Brd4 results in its degradation, thus docetaxel-associated Plk1 elevation is one approach to overcome resistance to Brd4 inhibitors. This hypothesis will be tested by pursuing three Specific Aims - (1) to dissect how Plk1 phosphorylation of Brd4 regulates AR signaling; (2) to understand how Brd4 phosphorylation contributes to PCa cell proliferation; and (3) to analyze clinical significance of Plk1-associated Brd4 phosphorylation. These complementary aims will be accomplished using biochemical analyses of signaling intermediates and employing genetic strategies with PCa mouse models, culture systems and PCa xenograft methodologies. The rationale for the research is that it will be the first to probe the importance of Plk1 to Brd4 and AR signaling and to examine whether a combination of docetaxel and Brd4 inhibitor ABBV-744 is a novel approach to treat ASI-resistant CRPC. This contribution is significant because it will (i) define the molecular mechanism by which Plk1 regulates Brd4 degradation and AR signaling; and (ii) validate docetaxel as a therapeutic agent to enhance the efficacy of Brd4 inhibitors.

题目：改进去势抵抗性前列腺癌的化疗