Targeting Androgen Receptor and PARP for Synthetic Lethality in CRPC

靶向雄激素受体和 PARP 来实现 CRPC 的综合致死性

基本信息

项目摘要

PROJECT SUMMARY (Project 3) Metastatic castration-resistant prostate cancer (mCRPC) remains an incurable disease for which novel molecular mechanism-based combination therapy strategies are needed. We identified an androgen receptor (AR)- and c-Myb–co-regulated DNA damage response (DDR) gene signature that is highly correlated with castration-resistance, metastasis, and reduced overall survival in mCRPC patients. In this DDR gene signature homologous recombination (HR) DNA repair genes and HR modulator (HRM) genes are highly represented. The relatively large percentage of HR/HRM genes in the DDR gene signature underscores the importance of this group of genes to prostate cancer progression. Our preliminary preclinical studies demonstrated that enzalutamide (ENZ), a 2nd-generation anti-androgen that blocks androgen from binding to the androgen receptor (AR), suppressed the expression of a majority of the HR/HRM genes and synergized with olaparib (OLA), a poly(ADP-ribose) polymerase 1 (PARP1) inhibitor in suppressing prostate cancer growth. Previously, OLA has been associated with synthetic lethality in multiple malignancies with BRCA1/2 or other HR gene deficiencies and its target, PARP1, plays a crucial role in base excision repair (BER) and was reported to function as an AR co-factor. In this project, we propose to test the hypothesis that targeting AR (ENZ) and PARP (OLA) in a “lead-in” strategy will generate synthetic lethality in mCRPC through ENZ-mediated downregulation of HR/HRM gene activity and OLA-mediated suppression of PARP’s enzymatic activity in BER and PARP’s cofactor role of AR transcriptional activity. The lead-in trial design will allow us to efficiently determine the clinical relevance of our biological findings by linking baseline to sequential modulation of target genes in individual cancers. We will test this hypothesis in three specific aims. Aim 1. Characterize the HR/HRM gene signature in bone marrow biopsies of men with mCRPC treated with enzalutamide and/or abiraterone, novel inhibitors of androgen signaling. Aim 2. Further characterize the synergistic potential of and identify predictive biomarkers of response to combination therapies that co-target AR (ENZ) and PARP function (OLA) using preclinical models. Aim 3. Conduct a clinical trial of treating CRPC patients with ENZ followed by the addition of the PARP inhibitor OLA to achieve greater therapeutic response and to correlate an ENZ-regulated HR/HRM gene signature to the therapeutic responses.
项目总结(项目3)

项目成果

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Timothy Charles Thompson其他文献

Timothy Charles Thompson的其他文献

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{{ truncateString('Timothy Charles Thompson', 18)}}的其他基金

Targeting Non-Canonical STING Signaling to Treat SPOP Mutant Castration-Resistant Prostate Cancer
靶向非经典 STING 信号传导治疗 SPOP 突变去势抵抗性前列腺癌
  • 批准号:
    10709358
  • 财政年份:
    2023
  • 资助金额:
    $ 30.91万
  • 项目类别:
Career Enhancement Program
职业提升计划
  • 批准号:
    10005149
  • 财政年份:
    2009
  • 资助金额:
    $ 30.91万
  • 项目类别:
Targeting Androgen Receptor and PARP for Synthetic Lethality in CRPC
靶向雄激素受体和 PARP 来实现 CRPC 的综合致死性
  • 批准号:
    10005152
  • 财政年份:
    2009
  • 资助金额:
    $ 30.91万
  • 项目类别:
GLIPR1-ATM Protein Therapy for Prostate Cancer
GLIPR1-ATM 蛋白治疗前列腺癌
  • 批准号:
    7743202
  • 财政年份:
    2009
  • 资助金额:
    $ 30.91万
  • 项目类别:
Developmental Research Program
发展研究计划
  • 批准号:
    8999526
  • 财政年份:
    2009
  • 资助金额:
    $ 30.91万
  • 项目类别:
Developmental Research Program
发展研究计划
  • 批准号:
    7743213
  • 财政年份:
    2009
  • 资助金额:
    $ 30.91万
  • 项目类别:
Developmental Research Program
发展研究计划
  • 批准号:
    10005148
  • 财政年份:
    2009
  • 资助金额:
    $ 30.91万
  • 项目类别:
Targeting Androgen Receptor and PARP for Synthetic Lethality in CRPC
靶向雄激素受体和 PARP 来实现 CRPC 的综合致死性
  • 批准号:
    8999530
  • 财政年份:
    2009
  • 资助金额:
    $ 30.91万
  • 项目类别:
GENE THERAPY FOR PROSTATE CANCER
前列腺癌的基因治疗
  • 批准号:
    6316543
  • 财政年份:
    2000
  • 资助金额:
    $ 30.91万
  • 项目类别:
GENE THERAPY FOR PROSTATE CANCER
前列腺癌的基因治疗
  • 批准号:
    6217437
  • 财政年份:
    1999
  • 资助金额:
    $ 30.91万
  • 项目类别:
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