NOTCH signaling controls transformation to androgen independent neuroendocrine prostate cancer

NOTCH信号控制向雄激素非依赖性神经内分泌前列腺癌的转化

基本信息

  • 批准号:
    10641672
  • 负责人:
  • 金额:
    $ 62.91万
  • 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:
    2019-05-22 至 2025-04-30
  • 项目状态:
    未结题

项目摘要

Androgen deprivation therapy (ADT) is effective in treating metastatic prostate adenocarcinoma (PADC), but all patients inevitably relapse with castrate resistant prostate cancer (CRPC). Most CRPCs remain dependent on androgen receptor (AR) signaling, but a significant fraction lack AR expression, become AR signaling independent, and aberrantly express neuroendocrine lineage markers (NEPC). The incidence of NEPC variants among CRPC has increased as more patients benefit from improved ADTs like enzalutamide and abiraterone acetate. This suggests increasingly stringent AR signaling blockade is driving development of NEPC. This is an important clinical problem because NEPC is aggressive and lethal; development of effective therapies is hampered by limited understanding of relevant molecular mechanisms. NEPC clearly arises from ARpos CRPC as they share clonal origin in patients that harbor both. We have determined that genetic inactivation of the RB1/TRP53 tumor suppressor genes cooperate to facilitate transformation of ARpos PADC to NEPC through derepression of epigenetic reprogramming factors. Inhibiting these reprogramming factors reverses NEPC transformation and restores ADT sensitivity, demonstrating that epigenetic changes are involved. We hypothesize that a change in NOTCH-ASCL1 signaling triggers the epigenetic reprogramming underlying NEPC transformation. This hypothesis has clinical ramifications as the pathway could conceivably be manipulated therapeutically to delay or reverse NEPC transformation, extending the duration of beneficial ADT clinical responses in some patients. We propose three specific aims using novel prostate cancer mouse models and unique human clinical specimens to test this hypothesis, characterize how PADC cells transform into NEPC cells, and explore novel therapeutic approaches for the treatment of this lethal form of prostate cancer. We will: 1) Test if NOTCH signaling is sufficient to maintain an androgen dependent PADC phenotype; 2) Characterize how prostate cancer cells transition from PADC to NEPC; 3) Determine whether epigenetic modulating drugs reverse NEPC transformation and ADT resistance via NOTCH-ASCL1 signaling. The long term goal of this project is to improve prostate cancer therapy by advancing mechanistic understanding of lineage plasticity as a mechanism of acquired therapeutic resistance.
雄激素剥夺疗法(ADT)治疗转移性前列腺癌(PADC)有效,但所有 患者不可避免地复发去势抵抗性前列腺癌(CRPC)。大多数CRPC仍然依赖于 雄激素受体(AR)信号传导,但显著部分缺乏AR表达,成为AR信号传导 独立和异常表达的神经内分泌谱系标志物(NEPC)。NEPC的发病率 CRPC中的变异增加,因为更多患者从改善的ADT(如enzalutamide)中获益, 醋酸阿比特龙这表明越来越严格的AR信号阻断正在推动 NEPC。这是一个重要的临床问题,因为NEPC是侵袭性和致命的;有效的治疗方法的发展。 治疗受到相关分子机制的有限理解的阻碍。NEPC显然源于 ARpos CRPC,因为它们在同时具有两者的患者中共享克隆起源。我们已经确定, RB 1/TRP 53肿瘤抑制基因的失活协同促进ARpos PADC转化为 NEPC通过表观遗传重编程因子的去抑制。抑制这些重编程因子 逆转NEPC转化并恢复ADT敏感性,表明表观遗传变化是 涉案我们假设NOTCH-ASCL 1信号通路的改变触发了表观遗传学的变化。 重新编程潜在的NEPC转化。这一假设具有临床分支,因为 可以通过治疗手段来延缓或逆转NEPC的转化, 某些患者的ADT有益临床应答持续时间。我们提出了三个具体的目标,使用新的 前列腺癌小鼠模型和独特的人类临床标本来测试这一假设, PADC细胞转化为NEPC细胞,并探索治疗这种疾病的新方法。 致命的前列腺癌我们将:1)测试NOTCH信号传导是否足以维持雄激素 依赖性PADC表型; 2)表征前列腺癌细胞如何从PADC转变为NEPC; 3) 确定表观遗传调节药物是否逆转NEPC转化和ADT耐药, NOTCH-ASCL 1信号传导。该项目的长期目标是通过以下方式改善前列腺癌治疗: 推进对谱系可塑性作为获得性治疗抗性机制的机械理解。

项目成果

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DAVID W. GOODRICH其他文献

DAVID W. GOODRICH的其他文献

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{{ truncateString('DAVID W. GOODRICH', 18)}}的其他基金

YAP1 and RB1 cooperate to regulate lung cancer lineage plasticity and therapeutic resistance
YAP1和RB1合作调节肺癌谱系可塑性和治疗耐药性
  • 批准号:
    10829724
  • 财政年份:
    2022
  • 资助金额:
    $ 62.91万
  • 项目类别:
Coordinating and Data Management Center for Acquired Resistance to Therapy Network
获得性治疗耐药网络协调和数据管理中心
  • 批准号:
    10516537
  • 财政年份:
    2022
  • 资助金额:
    $ 62.91万
  • 项目类别:
Coordinating and Data Management Center for Acquired Resistance to Therapy Network
获得性治疗耐药网络协调和数据管理中心
  • 批准号:
    10682495
  • 财政年份:
    2022
  • 资助金额:
    $ 62.91万
  • 项目类别:
NOTCH signaling controls transformation to androgen independent neuroendocrine prostate cancer
NOTCH信号控制向雄激素非依赖性神经内分泌前列腺癌的转化
  • 批准号:
    10346091
  • 财政年份:
    2019
  • 资助金额:
    $ 62.91万
  • 项目类别:
NOTCH signaling controls transformation to androgen independent neuroendocrine prostate cancer
NOTCH信号控制向雄激素非依赖性神经内分泌前列腺癌的转化
  • 批准号:
    10524127
  • 财政年份:
    2019
  • 资助金额:
    $ 62.91万
  • 项目类别:
NOTCH signaling controls transformation to androgen independent neuroendocrine prostate cancer
NOTCH信号控制向雄激素非依赖性神经内分泌前列腺癌的转化
  • 批准号:
    10759015
  • 财政年份:
    2019
  • 资助金额:
    $ 62.91万
  • 项目类别:
NOTCH signaling controls transformation to androgen independent neuroendocrine prostate cancer
NOTCH信号控制向雄激素非依赖性神经内分泌前列腺癌的转化
  • 批准号:
    10397535
  • 财政年份:
    2019
  • 资助金额:
    $ 62.91万
  • 项目类别:
(PQB5) Does the timing of Pten and Rb1 mutation affect prostate cancer phenotypes
(PQB5) Pten 和 Rb1 突变的时间是否影响前列腺癌表型
  • 批准号:
    8587206
  • 财政年份:
    2013
  • 资助金额:
    $ 62.91万
  • 项目类别:
(PQB5) Does the timing of Pten and Rb1 mutation affect prostate cancer phenotypes
(PQB5) Pten 和 Rb1 突变的时间是否影响前列腺癌表型
  • 批准号:
    8708795
  • 财政年份:
    2013
  • 资助金额:
    $ 62.91万
  • 项目类别:
The Role of Thoc1 in Normal Development and Cancer
Thoc1 在正常发育和癌症中的作用
  • 批准号:
    7332285
  • 财政年份:
    2007
  • 资助金额:
    $ 62.91万
  • 项目类别:

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钯催化的硅烷化乙酸烯丙酯新型有机转化的开发
  • 批准号:
    18K05101
  • 财政年份:
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