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:
- 金额:$ 63.45万
- 依托单位:
- 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:
- 关键词:AblationAgreementAndrogen ReceptorAndrogensApoptosisBindingBiochemicalBiometryCancer PatientCastrationCell CycleCellsChemoresistanceClinical ResearchClinical TrialsComplexCreativenessDataDevelopmentDiseaseDominant-Negative MutationDown-RegulationDrug resistanceEventFRAP1 geneFosteringGenetically Engineered MouseGoalsGrowthHealthHumanInvestigationKnock-outLaboratoriesMalignant NeoplasmsMalignant neoplasm of prostateMissionOperative Surgical ProceduresOutcomePLK1 genePathologyPathway interactionsPatient-Focused OutcomesPatientsPeptidesPharmaceutical PreparationsPhosphorylationPlayProstate Cancer therapyProteinsPublic HealthReceptor SignalingRegulationReportingRepressionResearchResistanceRoleSamplingSignal PathwaySignal TransductionSpecimenSystemTertiary Protein StructureTestingTherapeuticTumor SuppressionTumor Suppressor ProteinsUnited States National Institutes of HealthWorkXenograft procedureabirateronecastration resistant prostate cancerclinically significantdesigndocetaxeleffective therapyenzalutamidegenetic approachimprovedin vivoinhibitorinnovationmouse modelnew therapeutic targetnovelnovel strategiespatient derived xenograft modelprogrammed cell death protein 1prostate cancer cellprostate cancer progressionprotein degradationreceptor expressionsuccesstumor growthtumor initiationtumor 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
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
XIAOQI LIU其他文献
XIAOQI LIU的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ truncateString('XIAOQI LIU', 18)}}的其他基金
Plk1 as a prognostic biomarker for prostate cancer
Plk1 作为前列腺癌的预后生物标志物
- 批准号:
10664904 - 财政年份:2021
- 资助金额:
$ 63.45万 - 项目类别:
Plk1 as a prognostic biomarker for prostate cancer
Plk1 作为前列腺癌的预后生物标志物
- 批准号:
10437929 - 财政年份:2021
- 资助金额:
$ 63.45万 - 项目类别:
Enhancing the efficacy of androgen signaling inhibitors in prostate cancer
增强雄激素信号抑制剂在前列腺癌中的功效
- 批准号:
10659141 - 财政年份:2021
- 资助金额:
$ 63.45万 - 项目类别:
Plk1 as a prognostic biomarker for prostate cancer
Plk1 作为前列腺癌的预后生物标志物
- 批准号:
10306968 - 财政年份:2021
- 资助金额:
$ 63.45万 - 项目类别:
Enhancing the efficacy of androgen signaling inhibitors in prostate cancer
增强雄激素信号抑制剂在前列腺癌中的功效
- 批准号:
10294787 - 财政年份:2021
- 资助金额:
$ 63.45万 - 项目类别:
Enhancing the efficacy of androgen signaling inhibitors in prostate cancer
增强雄激素信号抑制剂在前列腺癌中的功效
- 批准号:
10427416 - 财政年份:2021
- 资助金额:
$ 63.45万 - 项目类别:
Improving chemotherapy of castration-resistant prostate cancer
改善去势抵抗性前列腺癌的化疗
- 批准号:
9973149 - 财政年份:2019
- 资助金额:
$ 63.45万 - 项目类别:
Improving chemotherapy of castration-resistant prostate cancer.
改善去势抵抗性前列腺癌的化疗。
- 批准号:
10663219 - 财政年份:2016
- 资助金额:
$ 63.45万 - 项目类别:
Enhancing anti-neoplastic activity of metformin in prostate cancer
增强二甲双胍在前列腺癌中的抗肿瘤活性
- 批准号:
9220731 - 财政年份:2016
- 资助金额:
$ 63.45万 - 项目类别:
Improving chemotherapy of castration-resistant prostate cancer.
改善去势抵抗性前列腺癌的化疗。
- 批准号:
10316730 - 财政年份:2016
- 资助金额:
$ 63.45万 - 项目类别:
相似海外基金
A study for cross borders Indonesian nurses and care workers: Case of Japan-Indonesia Economic Partnership Agreement
针对跨境印度尼西亚护士和护理人员的研究:日本-印度尼西亚经济伙伴关系协定的案例
- 批准号:
22KJ0334 - 财政年份:2023
- 资助金额:
$ 63.45万 - 项目类别:
Grant-in-Aid for JSPS Fellows
NSF-NOAA Interagency Agreement (IAA) for the Global Oscillations Network Group (GONG)
NSF-NOAA 全球振荡网络组 (GONG) 机构间协议 (IAA)
- 批准号:
2410236 - 财政年份:2023
- 资助金额:
$ 63.45万 - 项目类别:
Cooperative Agreement
Conditions for U.S. Agreement on the Closure of Contested Overseas Bases: Relations of Threat, Alliance and Base Alternatives
美国关于关闭有争议的海外基地协议的条件:威胁、联盟和基地替代方案的关系
- 批准号:
23K18762 - 财政年份:2023
- 资助金额:
$ 63.45万 - 项目类别:
Grant-in-Aid for Research Activity Start-up
MSI Smart Manufacturing Data Hub – Open Calls Grant Funding Agreement
MSI 智能制造数据中心 – 公开征集赠款资助协议
- 批准号:
900240 - 财政年份:2023
- 资助金额:
$ 63.45万 - 项目类别:
Collaborative R&D
Challenges of the Paris Agreement Exposed by the Energy Shift by External Factors: The Case of Renewable Energy Policies in Japan, the U.S., and the EU
外部因素导致的能源转移对《巴黎协定》的挑战:以日本、美国和欧盟的可再生能源政策为例
- 批准号:
23H00770 - 财政年份:2023
- 资助金额:
$ 63.45万 - 项目类别:
Grant-in-Aid for Scientific Research (B)
Continuation of Cooperative Agreement between U.S. Food and Drug Administration and S.C. Department of Health and Environmental Control (DHEC) for MFRPS Maintenance.
美国食品和药物管理局与南卡罗来纳州健康与环境控制部 (DHEC) 继续签订 MFRPS 维护合作协议。
- 批准号:
10829529 - 财政年份:2023
- 资助金额:
$ 63.45万 - 项目类别:
National Ecological Observatory Network Governing Cooperative Agreement
国家生态观测站网络治理合作协议
- 批准号:
2346114 - 财政年份:2023
- 资助金额:
$ 63.45万 - 项目类别:
Cooperative Agreement
The Kansas Department of Agriculture's Flexible Funding Model Cooperative Agreement for MFRPS Maintenance, FPTF, and Special Project.
堪萨斯州农业部针对 MFRPS 维护、FPTF 和特别项目的灵活资助模式合作协议。
- 批准号:
10828588 - 财政年份:2023
- 资助金额:
$ 63.45万 - 项目类别:
Robust approaches for the analysis of agreement between clinical measurements: development of guidance and software tools for researchers
分析临床测量之间一致性的稳健方法:为研究人员开发指南和软件工具
- 批准号:
MR/X029301/1 - 财政年份:2023
- 资助金额:
$ 63.45万 - 项目类别:
Research Grant
Doctoral Dissertation Research: Linguistic transfer in a contact variety of Spanish: Gender agreement production and attitudes
博士论文研究:西班牙语接触变体中的语言迁移:性别协议的产生和态度
- 批准号:
2234506 - 财政年份:2023
- 资助金额:
$ 63.45万 - 项目类别:
Standard Grant














{{item.name}}会员




