AR Gene Rearrangements and AR Signaling in Prostate Cancer

前列腺癌中的 AR 基因重排和 AR 信号转导

基本信息

  • 批准号:
    9246444
  • 负责人:
  • 金额:
    $ 31.01万
  • 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:
    2013-04-01 至 2018-03-31
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): Prostate cancer is the most frequently diagnosed male cancer and second leading cause of male cancer death. If primary treatment modalities are not capable of controlling the disease, inhibiting androgen receptor (AR) activity is an effective treatment for advanced prostate cancer patients. However, the duration of patient responses to AR-targeted therapy is variable, and all patients will ultimately develop resistance and progress to a castration-resistant form of the disease associated with morbidity and death. One important feature of castration-resistant prostate cancer (CRPC) is aberrant re-activation of AR transcriptional activity despite reduced levels of circulating androgens. This knowledge has led to the development of new therapies that inhibit mechanisms supporting residual transcriptional activity of the AR in CRPC. However, resistance remains a major limitation for these new AR-targeted agents. Because of the major need for new understanding and innovation in this area, the long-term objectives of this research are to determine the mechanisms that can support persistent AR transcriptional activity despite AR-targeted therapy, and to develop more effective strategies for treating and managing patients with CRPC. The central discovery driving the proposed studies is altered AR mRNA splicing, giving rise to COOH-terminally truncated AR variant (AR-V) proteins that achieve constitutive transcriptional activity in the complete absence of androgen stimulus. Synthesis of these AR-Vs has emerged as an important aspect of clinical CRPC progression, but mechanisms responsible for alterations in AR splicing are largely unknown. The overarching goal of this proposal is to understand the role of newly-discovered AR gene rearrangements in driving altered AR splicing patterns and efficient AR-V synthesis in CRPC. To achieve this goal, three specific aims are proposed. In Aim 1, an arsenal of customized next-generation DNA and RNA sequencing tools will be used to determine the spectrum of AR gene rearrangements and splicing alterations in tissues from patients with CRPC. In Aim 2, programmable nuclease technology will be used to experimentally engineer site-specific AR gene rearrangements in the prostate cancer genome. These genome-engineered cells will be studied to establish the links between architectural changes in the AR gene, aberrant AR mRNA splicing patterns, AR-V synthesis, and the CRPC phenotype. In Aim 3, AR gene rearrangements will be evaluated as new biomarkers for detecting AR-V driven CRPC cell populations in heterogeneous tumors, predicting responses to AR-targeted therapy, and monitoring the development of resistance during AR-targeted therapy. Success with these studies will establish the role of an entirely new class of AR gene alterations in prostate cancer progression, and provide new methods for evaluating AR gene status in prostate cancer cells. Knowledge and resources developed in this proposal will be important for developing new treatment regimens for prostate cancer based on an individual patient's unique AR gene architecture.
描述(由申请人提供):前列腺癌是最常诊断的男性癌症,也是男性癌症死亡的第二大原因。如果主要治疗方式不能控制疾病,抑制雄激素受体(AR)活性是晚期前列腺癌患者的有效治疗方法。然而,患者对AR靶向治疗的反应持续时间是可变的,所有患者最终都会产生耐药性,并进展为与发病和死亡相关的去势抵抗性疾病。去势抵抗性前列腺癌(CRPC)的一个重要特征是AR转录活性的异常再激活,尽管循环雄激素水平降低。这一知识导致了新疗法的开发,这些疗法抑制了支持CRPC中AR残留转录活性的机制。然而,耐药性仍然是这些新的AR靶向药物的主要限制。由于在这一领域需要新的理解和创新,本研究的长期目标是确定尽管AR靶向治疗仍能支持持续AR转录活性的机制,并开发更有效的治疗和管理CRPC患者的策略。推动拟议研究的中心发现是改变AR mRNA剪接,产生COOH末端截短的AR变体(AR-V)蛋白,在完全不存在雄激素刺激的情况下实现组成型转录活性。这些AR-V的合成已成为临床CRPC进展的一个重要方面,但负责AR剪接改变的机制在很大程度上是未知的。该提案的总体目标是了解新发现的AR基因重排在CRPC中驱动改变的AR剪接模式和有效的AR-V合成中的作用。为实现这一目标,提出了三个具体目标。在目标1中,将使用定制的下一代DNA和RNA测序工具库来确定CRPC患者组织中AR基因重排和剪接改变的谱。在目标2中,可编程核酸酶技术将用于实验性地设计前列腺癌基因组中的位点特异性AR基因重排。将研究这些基因组工程细胞,以建立AR基因结构变化、异常AR mRNA剪接模式、AR-V合成和CRPC表型之间的联系。在目标3中,AR基因重排将作为新的生物标志物进行评价,用于检测异质性肿瘤中AR-V驱动的CRPC细胞群,预测对AR靶向治疗的反应,并监测AR靶向治疗期间耐药性的发展。这些研究的成功将建立一种全新的AR基因改变在前列腺癌进展中的作用,并提供评估前列腺癌细胞中AR基因状态的新方法。本提案中开发的知识和资源对于基于个体患者独特的AR基因结构开发新的前列腺癌治疗方案将非常重要。

项目成果

期刊论文数量(0)
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Scott M. Dehm其他文献

CPSF1 inhibition promotes widespread use of intergenic polyadenylation sites and impairs glycolysis in prostate cancer cells
CPSF1 抑制促进了基因间多聚腺苷酸化位点的广泛使用,并损害了前列腺癌细胞中的糖酵解。
  • DOI:
    10.1016/j.celrep.2024.115211
  • 发表时间:
    2025-01-28
  • 期刊:
  • 影响因子:
    6.900
  • 作者:
    Kiel T. Tietz;Braedan M. McCluskey;Conor R. Miller;Yingming Li;Sarah A. Munro;Scott M. Dehm
  • 通讯作者:
    Scott M. Dehm
AR alterations inform circulating tumor DNA detection in metastatic castration resistant prostate cancer patients
AR 改变可提示转移性去势抵抗性前列腺癌患者循环肿瘤 DNA 的检测
  • DOI:
    10.1038/s41467-024-54847-1
  • 发表时间:
    2024-12-11
  • 期刊:
  • 影响因子:
    15.700
  • 作者:
    Todd P. Knutson;Bin Luo;Anna Kobilka;Jacqueline Lyman;Siyuan Guo;Sarah A. Munro;Yingming Li;Rakesh Heer;Luke Gaughan;Michael J. Morris;Himisha Beltran;Charles J. Ryan;Emmanuel S. Antonarakis;Andrew J. Armstrong;Susan Halabi;Scott M. Dehm
  • 通讯作者:
    Scott M. Dehm

Scott M. Dehm的其他文献

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{{ truncateString('Scott M. Dehm', 18)}}的其他基金

Molecular regulation and expression of Trop-2 in advanced prostate cancer: Identifying optimal therapeutic niches
晚期前列腺癌中 Trop-2 的分子调控和表达:确定最佳治疗领域
  • 批准号:
    10735996
  • 财政年份:
    2023
  • 资助金额:
    $ 31.01万
  • 项目类别:
Pharmacological Jak2 inhibition to overcome androgen receptor aberrations in prostate cancer
药理学 Jak2 抑制可克服前列腺癌中的雄激素受体畸变
  • 批准号:
    10443971
  • 财政年份:
    2022
  • 资助金额:
    $ 31.01万
  • 项目类别:
Pharmacological Jak2 inhibition to overcome androgen receptor aberrations in prostate cancer
药理学 Jak2 抑制可克服前列腺癌中的雄激素受体畸变
  • 批准号:
    10576409
  • 财政年份:
    2022
  • 资助金额:
    $ 31.01万
  • 项目类别:
Targeting early events in prostate cancer lineage plasticity
针对前列腺癌谱系可塑性的早期事件
  • 批准号:
    10587265
  • 财政年份:
    2022
  • 资助金额:
    $ 31.01万
  • 项目类别:
mRNA Polyadenylation in Prostate Cancer
前列腺癌中的 mRNA 多聚腺苷酸化
  • 批准号:
    10062626
  • 财政年份:
    2020
  • 资助金额:
    $ 31.01万
  • 项目类别:
AR Gene Rearrangements and AR Signaling in Prostate Cancer
前列腺癌中的 AR 基因重排和 AR 信号转导
  • 批准号:
    8826081
  • 财政年份:
    2013
  • 资助金额:
    $ 31.01万
  • 项目类别:
AR gene rearrangements and AR signaling in prostate cancer
前列腺癌中的 AR 基因重排和 AR 信号传导
  • 批准号:
    10363701
  • 财政年份:
    2013
  • 资助金额:
    $ 31.01万
  • 项目类别:
AR Gene Rearrangements and AR Signaling in Prostate Cancer
前列腺癌中的 AR 基因重排和 AR 信号转导
  • 批准号:
    8476830
  • 财政年份:
    2013
  • 资助金额:
    $ 31.01万
  • 项目类别:
AR gene rearrangements and AR signaling in prostate cancer
前列腺癌中的 AR 基因重排和 AR 信号传导
  • 批准号:
    9912109
  • 财政年份:
    2013
  • 资助金额:
    $ 31.01万
  • 项目类别:
AR Gene Rearrangements and AR Signaling in Prostate Cancer
前列腺癌中的 AR 基因重排和 AR 信号转导
  • 批准号:
    10656833
  • 财政年份:
    2013
  • 资助金额:
    $ 31.01万
  • 项目类别:

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雄激素受体:脂质代谢的主要调节因子
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    2023
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