ATR Dependency as a Novel Therapeutic Target in Lethal RB Deficient Prostate Cancer.

ATR 依赖性作为致命性 RB 缺陷前列腺癌的新治疗靶点。

基本信息

  • 批准号:
    10034539
  • 负责人:
  • 金额:
    $ 13.03万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2020
  • 资助国家:
    美国
  • 起止时间:
    2020-06-08 至 2020-09-30
  • 项目状态:
    已结题

项目摘要

PROJECT SUMMARY Metastatic prostate cancer (mPCa) is incurable and responsible for the majority of PC associated mortality. Therefore, there is a critical need to identify drivers of mPCa to enable early identification and interceptive therapeutic strategies to provide durable responses in patients. Androgen deprivation therapy (ADT) is the primary line of treatment for mPCa. ADT initially extends survival but is not curative as the patient’s tumor acquires castration resistance (mCRPC). A majority of mCRPC remain dependent on the function of the androgen receptor (AR), though due to the inclusion of more potent AR antagonist (eg: enzalutamide) has led to the emergence, in a subset of cases (approximately 20%), of resistance mechanisms independent of AR activity (CRPC-AI). CRPC-AI adapt to ADT via lineage plasticity rather than a result of resistant mutations, adopting a phenotype no longer reliant on AR expression and signaling. These tumors may display neuroendocrine features, a stem or basal cell-like phenotype, altered kinase signaling, and characteristic epigenetic alterations. Recently, we and others have characterized the molecular landscape of CRPC-AI and have identified and validated new therapeutic targets and drivers, including loss of Retinoblastoma-1 (RB) and TP53, and induction of specific epigenetic/reprogramming factors such as (Enhancer of Zeste Homolog 2) EZH2 and SOX2. Additionally, our work validated the importance of EZH2 reprogramming downstream of RB1 loss, driving lineage plasticity and resistance to ADT. Moreover, inhibition of EZH2 enabled lineage reversal and re-sensitized RB loss prostate cancer to ADT. Importantly, recent data from patients with mCRPC identified RB genetic aberrations as the strongest predictor of poor outcome. These data implicate RB as a dominant molecular mechanism driving lethal prostate cancer. Currently there is no therapeutic option to provide durable response in patients with RB loss-of-function (LOF). Therefore, there is a critical need to delineate downstream effectors of RB LOF so that therapeutic targets can be identified and validated in clinical trials. Specific to this application, our functional genomic screen has identified dependence on DNA damage repair kinases – specifically – ATR. This proposed work is innovative because it will provide deeper mechanistic knowledge of drivers of RB deficient prostate cancer and therapeutic options towards a currently untreatable phenotype. Through this work we will validate the ability of DDR kinase targeting to exacerbate DDR deficiency and to generate hypersensitivity in RB-deficient prostate models (Aim 1), determine the correlation between RB function, HR proficiency and response to M6620+carboplatin and docetaxel+carboplatin in preclinical models and clinical samples (Aim 2), and evaluate synergy of ATR kinase inhibition, EZH2 inhibition, and immune checkpoint blockade therapy in pre-clinical RB-deficient prostate mouse models (Aim 3). Ultimately, this information will enable us to gather sufficient preliminary evidence to make a compelling case to commence investigator-initiated multi-center clinical trials.
项目总结

项目成果

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Leigh Ellis其他文献

Leigh Ellis的其他文献

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{{ truncateString('Leigh Ellis', 18)}}的其他基金

Identifying EZH2-dependent vulnerabilities in RB deficient prostate cancer
鉴定 RB 缺陷型前列腺癌中 EZH2 依赖性脆弱性
  • 批准号:
    10410374
  • 财政年份:
    2021
  • 资助金额:
    $ 13.03万
  • 项目类别:
Identifying EZH2-dependent vulnerabilities in RB deficient prostate cancer
鉴定 RB 缺陷型前列腺癌中 EZH2 依赖性脆弱性
  • 批准号:
    10154294
  • 财政年份:
    2021
  • 资助金额:
    $ 13.03万
  • 项目类别:
ATR Dependency as a Novel Therapeutic Target in Lethal RB Deficient ProstateCancer
ATR 依赖性作为致命性 RB 缺陷前列腺癌的新治疗靶点
  • 批准号:
    10304098
  • 财政年份:
    2020
  • 资助金额:
    $ 13.03万
  • 项目类别:
ATR Dependency as a Novel Therapeutic Target in Lethal RB Deficient ProstateCancer
ATR 依赖性作为致命性 RB 缺陷前列腺癌的新治疗靶点
  • 批准号:
    10186723
  • 财政年份:
    2020
  • 资助金额:
    $ 13.03万
  • 项目类别:
ATR Dependency as a Novel Therapeutic Target in Lethal RB Deficient ProstateCancer
ATR 依赖性作为致命性 RB 缺陷前列腺癌的新治疗靶点
  • 批准号:
    10472549
  • 财政年份:
    2020
  • 资助金额:
    $ 13.03万
  • 项目类别:
Exploiting RB1 deficiency for the treatment of lethal neuroendocrine prostate cancer
利用 RB1 缺陷治疗致命性神经内分泌前列腺癌
  • 批准号:
    9763338
  • 财政年份:
    2016
  • 资助金额:
    $ 13.03万
  • 项目类别:
Novel Mouse Models to define Genetic Drivers of Aggressive Prostate Cancer
定义侵袭性前列腺癌遗传驱动因素的新型小鼠模型
  • 批准号:
    9461668
  • 财政年份:
    2016
  • 资助金额:
    $ 13.03万
  • 项目类别:
Exploiting RB1 deficiency for the treatment of lethal neuroendocrine prostate cancer
利用 RB1 缺陷治疗致命性神经内分泌前列腺癌
  • 批准号:
    9338195
  • 财政年份:
    2016
  • 资助金额:
    $ 13.03万
  • 项目类别:
Exploiting RB1 deficiency for the treatment of lethal neuroendocrine prostate cancer
利用 RB1 缺陷治疗致命性神经内分泌前列腺癌
  • 批准号:
    9152986
  • 财政年份:
    2016
  • 资助金额:
    $ 13.03万
  • 项目类别:

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