Aberrant tumor metabolism that enables AR antagonist-resistant prostate cancer

肿瘤代谢异常导致 AR 拮抗剂耐药前列腺癌

基本信息

  • 批准号:
    10521260
  • 负责人:
  • 金额:
    $ 7.35万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2019
  • 资助国家:
    美国
  • 起止时间:
    2019-12-01 至 2023-06-09
  • 项目状态:
    已结题

项目摘要

Project Summary Prostate cancer depends on androgens and the androgen receptor (AR) for growth and progression. Metastatic tumors are usually initially treated with androgen deprivation therapy by way of medical or surgical castration; however, tumors eventually recur as castration-resistant prostate cancer (CRPC), which progresses due to the intratumoral generation of testosterone and/or dihydrotestosterone and AR stimulation. The identification of these mechanisms and the requirement for sustained AR stimulation has led to the development of enzalutamide, which is a next-generation hormonal therapy that directly and potently antagonizes AR and thereby extends survival for men with metastatic CRPC. Unfortunately, responses to enzalutamide are temporary and resistance eventually leads to death. Enzalutamide resistance is therefore a major and widespread clinical problem for patients with advanced prostate cancer. Recent evidence suggests that enzalutamide resistance is driven by an up-regulation of the glucocorticoid receptor (GR), which re-establishes the expression of 50% of genes that are usually responsive to AR stimulation. Unfortunately, the clinical application of this finding is challenged by the fact that complete and systemic GR ablation is lethal in humans. However, identification of a tumor tissue-specific mechanism that enables GR stimulation might provide a potential therapeutic target that would not compromise the patient. We hypothesize that GR stimulation that occurs with AR antagonist resistance is accompanied by a tumor-specific metabolic mechanism that furnishes abundant local concentrations of cortisol, a GR agonist. Our preliminary data demonstrate that 11β-hydroxysteroid dehydrogenase-2 (11βHSD2), the enzyme that is primarily responsible for cortisol inactivation, is lost with AR antagonist resistance, resulting in augmented local cortisol concentrations. Furthermore, we hypothesize that blocking this metabolic mechanism would reverse GR stimulation and thereby reinstate responsiveness to AR antagonist therapy. Our preliminary data suggest that replacing 11βHSD2 enzymatic function, by either restoring 11βHSD2 expression or blocking the machinery that is required for 11βHSD2 protein degradation, reverses the metabolic phenotype and restores sensitivity to AR antagonist therapy. In Aim 1, we will determine the metabolic phenotype conferred by treatment with next- generation hormonal therapies for CRPC. In Aim 2, we will identify the molecular mechanisms that regulate glucocorticoid metabolism in AR antagonist resistance. In Aim 3, we will determine the therapeutic significance of restoring the baseline metabolic phenotype in AR antagonist resistance. Together, these studies will identify and clinically validate mechanisms that drive AR antagonist resistance. It is anticipated that this work will lead to the identification of tumor-specific mechanisms of resistance to next-generation hormonal therapies that are pharmacologically targetable and to the eventual development of new treatment strategies for the lethal form of prostate cancer.
项目摘要 前列腺癌的生长和进展依赖于雄激素和雄激素受体(AR)。 转移性肿瘤通常最初通过药物或手术的方式用雄激素剥夺疗法治疗。 然而,肿瘤最终复发为去势抵抗性前列腺癌(CRPC),其进展是由于 肿瘤内产生睾酮和/或二氢睾酮以及AR刺激。识别 这些机制和对持续AR刺激的需求导致了 恩杂鲁胺,这是一种下一代激素疗法,可直接有效地拮抗AR,从而 延长转移性CRPC男性患者的生存期。不幸的是,Enzalutamide的反应是暂时的, 反抗最终导致死亡。因此,Enzalutamide耐药是一个主要且广泛的临床问题 治疗晚期前列腺癌 最近的证据表明,恩杂鲁胺耐药是由糖皮质激素的上调驱动的 受体(GR),其重建通常对AR刺激有反应的50%基因的表达。 不幸的是,这一发现的临床应用受到以下事实的挑战: 消融对人类是致命的。然而,确定肿瘤组织特异性机制,使GR 刺激可能会提供一个潜在的治疗目标,而不会损害患者的健康。 我们假设,AR拮抗剂抵抗时发生的GR刺激伴随着 肿瘤特异性的代谢机制,使大量的皮质醇,GR激动剂的局部浓度降低。我们 初步数据表明,11β-羟基类固醇脱氢酶-2(11β HSD 2),主要是 负责皮质醇失活,随着AR拮抗剂抵抗而丧失,导致局部皮质醇增加 浓度的此外,我们假设阻断这种代谢机制将逆转GR 刺激,从而恢复对AR拮抗剂治疗的反应性。我们的初步数据显示, 通过恢复11 β HSD 2的表达或阻断11β HSD 2的表达机制来替代11β HSD 2的酶功能, 是11β HSD 2蛋白降解所必需的,逆转代谢表型并恢复对AR的敏感性 拮抗剂治疗。在目标1中,我们将确定通过用下一种药物治疗所赋予的代谢表型。 CRPC的激素治疗。在目标2中,我们将确定调节 糖皮质激素代谢在AR拮抗剂抵抗中的作用。在目标3中,我们将确定 恢复AR拮抗剂抗性的基线代谢表型。总之,这些研究将确定 并在临床上验证驱动AR拮抗剂抗性的机制。预计这项工作将导致 确定对下一代激素疗法的耐药性的肿瘤特异性机制, 并最终开发出针对致命形式的 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 }}

Nima Sharifi其他文献

Nima Sharifi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('Nima Sharifi', 18)}}的其他基金

CYP17A1-independent androgen synthesis and prostate cancer resistance to next-generation hormonal therapy
CYP17A1独立的雄激素合成和前列腺癌对下一代激素治疗的抵抗
  • 批准号:
    10557156
  • 财政年份:
    2022
  • 资助金额:
    $ 7.35万
  • 项目类别:
CYP17A1-independent androgen synthesis and prostate cancer resistance to next-generation hormonal therapy
CYP17A1独立的雄激素合成和前列腺癌对下一代激素治疗的抵抗
  • 批准号:
    10442233
  • 财政年份:
    2022
  • 资助金额:
    $ 7.35万
  • 项目类别:
CYP17A1-independent androgen synthesis and prostate cancer resistance to next-generation hormonal therapy
CYP17A1独立的雄激素合成和前列腺癌对下一代激素治疗的抵抗
  • 批准号:
    10842022
  • 财政年份:
    2022
  • 资助金额:
    $ 7.35万
  • 项目类别:
Aberrant tumor metabolism that enables AR antagonist-resistant prostate cancer
肿瘤代谢异常导致 AR 拮抗剂耐药前列腺癌
  • 批准号:
    9886389
  • 财政年份:
    2019
  • 资助金额:
    $ 7.35万
  • 项目类别:
Aberrant tumor metabolism that enables AR antagonist-resistant prostate cancer
异常的肿瘤代谢导致 AR 拮抗剂对前列腺癌产生耐药性
  • 批准号:
    10847199
  • 财政年份:
    2019
  • 资助金额:
    $ 7.35万
  • 项目类别:
Aberrant tumor metabolism that enables AR antagonist-resistant prostate cancer
肿瘤代谢异常导致 AR 拮抗剂耐药前列腺癌
  • 批准号:
    10058257
  • 财政年份:
    2019
  • 资助金额:
    $ 7.35万
  • 项目类别:
Aberrant tumor metabolism that enables AR antagonist-resistant prostate cancer
肿瘤代谢异常导致 AR 拮抗剂耐药前列腺癌
  • 批准号:
    10308051
  • 财政年份:
    2019
  • 资助金额:
    $ 7.35万
  • 项目类别:
Elucidating a novel molecular biomarker for castration-resistant prostate cancer
阐明去势抵抗性前列腺癌的新型分子生物标志物
  • 批准号:
    10113548
  • 财政年份:
    2018
  • 资助金额:
    $ 7.35万
  • 项目类别:
Elucidating a novel molecular biomarker for castration-resistant prostate cancer
阐明去势抵抗性前列腺癌的新型分子生物标志物
  • 批准号:
    10372921
  • 财政年份:
    2018
  • 资助金额:
    $ 7.35万
  • 项目类别:
Elucidating a novel molecular biomarker for castration-resistant prostate cancer
阐明去势抵抗性前列腺癌的新型分子生物标志物
  • 批准号:
    9900724
  • 财政年份:
    2018
  • 资助金额:
    $ 7.35万
  • 项目类别:

相似海外基金

Targeted ablation of cerebral atherosclerosis using supramolecular self-assembly
利用超分子自组装靶向消融脑动脉粥样硬化
  • 批准号:
    24K21101
  • 财政年份:
    2024
  • 资助金额:
    $ 7.35万
  • 项目类别:
    Grant-in-Aid for Early-Career Scientists
心房細動に対するPulsed Field Ablationの組織創傷治癒過程を明らかにする網羅的研究
阐明房颤脉冲场消融组织伤口愈合过程的综合研究
  • 批准号:
    24K11201
  • 财政年份:
    2024
  • 资助金额:
    $ 7.35万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
遅延造影心臓MRIによる心房細動Ablation冷却効果の比較:28 vs. 31 mm Cryoballoon
使用延迟对比增强心脏 MRI 比较房颤消融冷却效果:28 毫米与 31 毫米 Cryoballoon
  • 批准号:
    24K11281
  • 财政年份:
    2024
  • 资助金额:
    $ 7.35万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
InSPACE-VT_Development and Validation of Virtual Pace Mapping to Guide Catheter Ablation of Ventricular Tachycardia
InSPACE-VT_虚拟起搏测绘的开发和验证以指导室性心动过速导管消融
  • 批准号:
    EP/Z001145/1
  • 财政年份:
    2024
  • 资助金额:
    $ 7.35万
  • 项目类别:
    Fellowship
CAREER: Heat Penetration Depth and Direction Control with Closed-Loop Device for Precision Ablation
职业:利用闭环装置控制热穿透深度和方向,实现精确烧蚀
  • 批准号:
    2338890
  • 财政年份:
    2024
  • 资助金额:
    $ 7.35万
  • 项目类别:
    Continuing Grant
Collaborative Research: RUI: Frontal Ablation Processes on Lake-terminating Glaciers and their Role in Glacier Change
合作研究:RUI:湖终止冰川的锋面消融过程及其在冰川变化中的作用
  • 批准号:
    2334777
  • 财政年份:
    2024
  • 资助金额:
    $ 7.35万
  • 项目类别:
    Continuing Grant
Collaborative Research: RUI: Frontal Ablation Processes on Lake-terminating Glaciers and their Role in Glacier Change
合作研究:RUI:湖终止冰川的锋面消融过程及其在冰川变化中的作用
  • 批准号:
    2334775
  • 财政年份:
    2024
  • 资助金额:
    $ 7.35万
  • 项目类别:
    Continuing Grant
Collaborative Research: RUI: Frontal Ablation Processes on Lake-terminating Glaciers and their Role in Glacier Change
合作研究:RUI:湖终止冰川的锋面消融过程及其在冰川变化中的作用
  • 批准号:
    2334776
  • 财政年份:
    2024
  • 资助金额:
    $ 7.35万
  • 项目类别:
    Continuing Grant
Cryo laser-ablation system (157+193nm) with 'triple-quad' plasma mass spectrometer, Cryo-LA-ICPMS/MS
带有“三重四极杆”等离子体质谱仪、Cryo-LA-ICPMS/MS 的冷冻激光烧蚀系统 (157 193nm)
  • 批准号:
    515081333
  • 财政年份:
    2023
  • 资助金额:
    $ 7.35万
  • 项目类别:
    Major Research Instrumentation
MRI: Acquisition of a Laser Ablation - Inductively Coupled Plasma - Triple Quadrupole - Mass Spectrometer (LA-ICP-QQQ-MS) System For Research and Education
MRI:获取用于研究和教育的激光烧蚀 - 电感耦合等离子体 - 三重四极杆 - 质谱仪 (LA-ICP-MS/MS) 系统
  • 批准号:
    2320040
  • 财政年份:
    2023
  • 资助金额:
    $ 7.35万
  • 项目类别:
    Standard Grant
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了