Androgen Receptor Action in Castration Resistant Prostate Cancer
雄激素受体在去势抵抗性前列腺癌中的作用
基本信息
- 批准号:10363638
- 负责人:
- 金额:$ 142.94万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2013
- 资助国家:美国
- 起止时间:2013-05-24 至 2024-01-31
- 项目状态:已结题
- 来源:
- 关键词:Androgen ReceptorAndrogensAutomobile DrivingBasic ScienceBenchmarkingCYP17A1 geneCancer RelapseCastrationCell ProliferationCell SurvivalCellsChromatinClinical ResearchClinical TrialsDataDependenceEZH2 geneEnzymesEpigenetic ProcessEssential GenesFeedbackFoundationsFundingGenesGenetic TranscriptionGoalsGrowthLengthMalignant neoplasm of prostateMediatingMedical CastrationModelingMutationPathogenesisPathway interactionsPatientsPhosphorylationPhosphotransferasesPost-Translational Protein ProcessingPre-Clinical ModelProstate Cancer therapyProtein KinaseRNA SplicingReagentRelapseResearch PersonnelResistanceResourcesRoleTechnologyTestingTherapeuticTimeTranslational ResearchVariantabirateroneantagonistcastration resistant prostate cancerclinically relevantenzalutamidegenetic corepressorhormone therapyinhibitorintratumoral androgenkinase inhibitormenneoplastic cellnovelnovel strategiesoverexpressionpreventprogramsprostate cancer cellreceptor expressionresistance mechanismresponsescreeningsuccesstargeted treatmenttherapeutic targettherapy resistanttumortumor growth
项目摘要
This is a revised competitive renewal application for our P01 entitled “Androgen Receptor Action In Castration
Resistant Prostate Cancer”. The past several years have seen a paradigm shift in prostate cancer (PCa)
therapy, as it is now clear that the androgen receptor (AR) remains active and is a therapeutic target in PCa
that relapses after surgical or medical castration (castration-resistant prostate cancer, CRPC). Previous basic,
translational and clinical research conducted by investigators in this P01 proposal made major contributions to
this paradigm shift by elucidating fundamental mechanisms of AR action and mechanisms of castration-
resistance in patients. The CYP17A1 inhibitor abiraterone, and the AR antagonist enzalutamide, are now
standard second line hormonal therapies for men who relapse after castration. Unfortunately, most men who
respond to these therapies will relapse within 1-2 years. Significantly, while a subset of abiraterone or
enzalutamide-resistant PCa may become AR independent, recent results from investigators in this P01 and
others indicate that most continue to express high levels of AR that appears to be transcriptionally active.
Therefore, a major hypothesis in this proposal is that AR activity still persists and is contributing to tumor
growth in abiraterone and enzalutamide-resistant PCa. Moreover, we hypothesize that adaptations made by
PCa cells in response to AR targeted therapies create vulnerabilities that can be exploited therapeutically.
Hence, overall program goals are to elucidate clinically relevant mechanisms that contribute to CRPC and
abiraterone/enzalutamide-resistance, to identify therapeutic approaches that can overcome these resistance
mechanisms and/or exploit new vulnerabilities, and to assess these therapeutic approaches in preclinical
models that can form foundations for clinical trials. The Projects are as follows: 1) Determining and Exploiting
Mechanisms of AR-Mediated Suppression of Cell, 2) Mechanisms Driving AR Full Length and Splice Variant
Activities and Antagonist Resistance, 3) Protein Kinases Influencing Androgen Receptor in Castrate Resistant
Prostate Cancer, 4) Identification of Essential Genes Underlying AR Activity in Antagonist-Resistant CRPC.
这是一个修改后的竞争性更新申请,我们的P01题为“雄激素受体作用在去势
耐药前列腺癌”。在过去的几年里,前列腺癌(PCa)发生了范式转变。
治疗,因为现在很清楚雄激素受体(AR)保持活性,是PCa的治疗靶点
手术或药物去势后复发的前列腺癌(去势抵抗性前列腺癌,CRPC)。以前的基本,
研究者在P01提案中进行的转化和临床研究对以下方面做出了重大贡献:
通过阐明AR作用的基本机制和去势机制,
患者的抵抗力。CYP 17 A1抑制剂阿比特龙和AR拮抗剂恩杂鲁胺,现在是
标准二线激素治疗的男性谁复发后阉割。不幸的是,大多数男人
对这些治疗有效的患者将在1-2年内复发。值得注意的是,虽然阿比特龙或
本P01研究人员的最新结果显示,对恩杂鲁胺耐药的PCa可能不依赖AR,
其他研究表明,大多数继续表达高水平的AR,其似乎是转录活性的。
因此,该提案中的一个主要假设是AR活性仍然存在,并且有助于肿瘤的发生。
阿比特龙和恩杂鲁胺耐药PCa的生长。此外,我们假设,
PCa细胞对AR靶向治疗的反应产生了可以在治疗上利用的漏洞。
因此,总体计划目标是阐明有助于CRPC的临床相关机制,
阿比特龙/恩杂鲁胺耐药性,以确定可以克服这些耐药性的治疗方法
机制和/或利用新的弱点,并评估这些治疗方法在临床前
可以为临床试验奠定基础的模型。本课题的研究内容如下:1)确定和开发
AR介导的细胞抑制机制,2)驱动AR全长和剪接变体的机制
活性和拮抗剂抗性,3)影响去势抵抗的雄激素受体的蛋白激酶
前列腺癌,4)在拮抗剂抗性CRPC中作为AR活性基础的必需基因的鉴定。
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)
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Steven P. Balk其他文献
Recognition of cluster of differentiation 1 antigens by human CD4−CD8>− cytolytic T lymphocyte
人 CD4−CD8>−细胞毒性 T 淋巴细胞对分化簇 1 抗原簇的识别
- DOI:
10.1038/341447a0 - 发表时间:
1989-10-05 - 期刊:
- 影响因子:48.500
- 作者:
Steven Porcelli;Michael B. Brenner;Julia L. Greenstein;Cox Terhorst;Steven P. Balk;Paul A. Bleicher - 通讯作者:
Paul A. Bleicher
Specific reversal of cytolytic T cell-target cell functional binding is induced by free target cells.
游离靶细胞诱导溶细胞性 T 细胞与靶细胞功能结合的特异性逆转。
- DOI:
10.4049/jimmunol.127.1.51 - 发表时间:
1981 - 期刊:
- 影响因子:4.4
- 作者:
Steven P. Balk;M. Mescher - 通讯作者:
M. Mescher
BH3 mimetics targeting BCL-XL have efficacy in solid tumors with RB1 loss and replication stress
靶向 BCL-XL 的 BH3 模拟物在具有 RB1 缺失和复制应激的实体瘤中具有疗效
- DOI:
10.1038/s41467-025-60238-x - 发表时间:
2025-05-28 - 期刊:
- 影响因子:15.700
- 作者:
Andreas Varkaris;Keshan Wang;Mannan Nouri;Nina Kozlova;Daniel R. Schmidt;Anastasia Stavridi;Seiji Arai;Nicholas Ambrosio;Larysa Poluben;Juan M. Jimenez-Vacas;Daniel Westaby;Juliet Carmichael;Fang Xie;Ines Figueiredo;Lorenzo Buroni;Antje Neeb;Bora Gurel;Nicholas Chevalier;Lisha Brown;Olga Voznesensky;Shao-Yong Chen;Joshua W. Russo;Xin Yuan;Dejan Juric;Himisha Beltran;Johann S. De Bono;Matthew G. Vander Heiden;David J. Einstein;Taru Muranen;Eva Corey;Adam Sharp;Steven P. Balk - 通讯作者:
Steven P. Balk
Inhibiteurs de kinase moelle osseuse sur chromosome x (bmx) et leurs utilisations
X 染色体上的骨摩尔激酶抑制剂 (bmx) 及其用途
- DOI:
- 发表时间:
2013 - 期刊:
- 影响因子:0
- 作者:
Nathanael S. Gray;Steven P. Balk;Qingsong Liu;Sen Chen - 通讯作者:
Sen Chen
665 EFFECT OF NEOADJUVANT ABIRATERONE ACETATE PLUS LEUPROLIDE ACETATE ON PSA, PATHOLOGIC RESPONSE, AND INTRAPROSTATIC/SERUM ANDROGEN LEVELS IN LOCALIZED HIGH-RISK PROSTATE CANCER: RESULTS OF A RANDOMIZED PHASE 2 STUDY
- DOI:
10.1016/j.juro.2013.02.220 - 发表时间:
2013-04-01 - 期刊:
- 影响因子:
- 作者:
Jerome P. Richie;Robert B. Montgomery;Christopher J. Logothetis;Glenn J. Bubley;Bruce L. Dalkin;Martin G. Sanda;Massimo F. Loda;Rosina T. Lis;Lawrence D. True;Patricia Troncoso;Elizabeth M. Genega;Steven P. Balk;Elahe A. Mostaghel;Trevor M. Penning;Peter S. Nelson;Wanling Xie;Christopher M. Haqq;NamPhuong Tran;Weimin Peng;Daniel Tamae - 通讯作者:
Daniel Tamae
Steven P. Balk的其他文献
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{{ truncateString('Steven P. Balk', 18)}}的其他基金
WNT5a/ROR2-Mediated Hippo Pathway Activation in Prostate Cancer
前列腺癌中 WNT5a/ROR2 介导的 Hippo 通路激活
- 批准号:
10734173 - 财政年份:2023
- 资助金额:
$ 142.94万 - 项目类别:
Enhancing the Efficacy of Docetaxel in Prostate Cancer
增强多西紫杉醇治疗前列腺癌的疗效
- 批准号:
10665071 - 财政年份:2022
- 资助金额:
$ 142.94万 - 项目类别:
Prostate Cancer Vulnerabilities to BH3 Mimetic Drugs
前列腺癌对 BH3 模拟药物的脆弱性
- 批准号:
10407648 - 财政年份:2021
- 资助金额:
$ 142.94万 - 项目类别:
Prostate Cancer Vulnerabilities to BH3 Mimetic Drugs
前列腺癌对 BH3 模拟药物的脆弱性
- 批准号:
10279279 - 财政年份:2021
- 资助金额:
$ 142.94万 - 项目类别:
SOX9 Mediation of AR and ERG Driven Prostate Cancer
SOX9 介导 AR 和 ERG 驱动的前列腺癌
- 批准号:
9477598 - 财政年份:2014
- 资助金额:
$ 142.94万 - 项目类别:
SOX9 Mediation of AR and ERG Driven Prostate Cancer
SOX9 介导 AR 和 ERG 驱动的前列腺癌
- 批准号:
8653225 - 财政年份:2014
- 资助金额:
$ 142.94万 - 项目类别:
SOX9 Mediation of AR and ERG Driven Prostate Cancer
SOX9 介导 AR 和 ERG 驱动的前列腺癌
- 批准号:
9269164 - 财政年份:2014
- 资助金额:
$ 142.94万 - 项目类别:
Androgen Receptor Action in Castration Resistant Prostate Cancer
雄激素受体在去势抵抗性前列腺癌中的作用
- 批准号:
8475909 - 财政年份:2013
- 资助金额:
$ 142.94万 - 项目类别:
Project 2: Mechanisms Driving AR Full Length and Splice Variant Activities and Antagonist Resistance
项目 2:驱动 AR 全长和剪接变体活动和拮抗剂耐药性的机制
- 批准号:
10363640 - 财政年份:2013
- 资助金额:
$ 142.94万 - 项目类别:
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