Treatment-Induced Phenotypic Reprogramming in Prostate Cancer

前列腺癌治疗诱导的表型重编程

基本信息

项目摘要

The androgen receptor (AR) is a critical driver of therapeutic response in patients with metastatic castration- resistant prostate cancer (mCRPC). Androgen deprivation therapy (ADT) and AR-targeting, particularly in combination with microtubule-targeting taxane chemotherapy, offers survival benefits in mCRPC patients. However, therapeutic resistance invariably develops, leading to mortality. Understanding the mechanisms underlying resistance is critical to improving therapeutic outcomes. Our work and others' established that AR nuclear localization is inhibited by docetaxel (1st line taxane chemotherapy) in androgen-sensitive prostate tumors. In contrast, CRPCs express AR splice variants that remain capable of nuclear trafficking, contributing to taxane resistance. Signaling interactions between androgens/AR and transforming growth factor-β (TGF-β) determine prostate tumor growth and invasion by regulating apoptosis and epithelial-mesenchymal transition (EMT). We recently found that cabazitaxel (2nd line taxane chemotherapy) can reverse EMT, resulting in a mesenchymal-epithelial transition (MET) and kinesin-mediated multi-nucleation, without affecting nuclear AR in in vitro and in vivo prostate cancer models. This work provided the first evidence that cabazitaxel induces phenotypic changes leading to prostate tumor re-differentiation (in addition to apoptosis) dictated by androgens and TGF-β. Here, we hypothesize that treatment with cabazitaxel causes apoptosis in some prostate tumor cells but also diversifies surviving cells into a re-differentiated state (via MET) that confers therapeutic resistance while retaining AR and kinesin activity. We will test this hypothesis by assessing if MET-mediated phenotypic reprogramming of prostate cancer epithelial cells drives therapeutic resistance to taxane chemotherapy/ADT combinations, and if this resistance can be overcome by TGF-β blockade. Three Specific Aims will be addressed: Specific Aim 1 will delineate the role of AR cross-talk with TGF-β in programming prostate tumor MET in response to cabazitaxel in models of CRPC. Specific Aim 2 will determine the mechanisms via which prostate tumor cells undergo taxane-mediated re-differentiation to overcome therapeutic resistance in pre-clinical models of advanced prostate cancer. Specific Aim 3 will test the effect of inhibition of kinesins and centrosome clustering on microtubule-facilitated AR degradation, to sensitize prostate tumors to cabazitaxel. The proposed project will provide new insights into the contribution of TGF-β, AR, and kinesins in taxane-mediated phenotypic changes and define treatment sequencing to overcome resistance in recurrent disease.
雄激素受体(AR)是转移性去势患者治疗反应的关键驱动因素- 耐药前列腺癌(mCRPC)。雄激素剥夺治疗(ADT)和AR靶向治疗,特别是在 联合微管靶向紫杉烷化疗,为mCRPC患者提供生存获益。 然而,治疗抗性总是会发展,导致死亡。了解机制 潜在的耐药性对改善治疗结果至关重要。我们的工作和其他人的工作表明, 雄激素敏感性前列腺中多西他赛(一线紫杉烷化疗)抑制核定位 肿瘤的相反,CRPC表达AR剪接变体,其仍然能够进行核运输,有助于 紫杉烷耐药性雄激素/AR和转化生长因子-β(TGF-β)之间的信号相互作用 通过调节细胞凋亡和上皮-间质转化来决定前列腺肿瘤的生长和侵袭 (EMT)。我们最近发现卡巴他赛(二线紫杉烷化疗)可以逆转EMT, 间充质-上皮转化(MET)和驱动蛋白介导的多核化,而不影响核AR。 体外和体内前列腺癌模型。这项工作提供了第一个证据,卡巴他赛诱导 表型变化导致前列腺肿瘤再分化(除细胞凋亡外),由雄激素决定 和TGF-β。在此,我们假设卡巴他赛治疗可导致某些前列腺肿瘤细胞凋亡 而且还使存活细胞多样化为再分化状态(通过MET),其赋予治疗抗性, 保留AR和驱动蛋白活性。我们将通过评估MET介导的表型 前列腺癌上皮细胞的重编程驱动对紫杉烷化疗/ADT的治疗抗性 联合使用,以及这种抗性是否可以通过TGF-β阻断来克服。将讨论三个具体目标: 具体目标1将描述AR与TGF-β的串扰在编程前列腺肿瘤MET中的作用, 在CRPC模型中对卡巴他赛的反应。具体目标2将确定前列腺 肿瘤细胞经历紫杉烷介导的再分化以克服临床前模型中的治疗抗性 晚期前列腺癌的症状具体目标3将测试抑制驱动蛋白和中心体的效果 聚集在微管促进的AR降解上,以使前列腺肿瘤对卡巴他赛敏感。拟议 该项目将为TGF-β,AR和驱动蛋白在紫杉烷介导的表型转化中的作用提供新的见解。 改变和确定治疗顺序,以克服复发性疾病的耐药性。

项目成果

期刊论文数量(16)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
The Evolving Clinical Management of Genitourinary Cancers Amid the COVID-19 Pandemic.
  • DOI:
    10.3389/fonc.2021.734963
  • 发表时间:
    2021
  • 期刊:
  • 影响因子:
    4.7
  • 作者:
    Izadmehr S;Lundon DJ;Mohamed N;Katims A;Patel V;Eilender B;Mehrazin R;Badani KK;Sfakianos JP;Tsao CK;Wiklund P;Oh WK;Cordon-Cardo C;Tewari AK;Galsky MD;Kyprianou N
  • 通讯作者:
    Kyprianou N
Non-Coding RNAs Set a New Phenotypic Frontier in Prostate Cancer Metastasis and Resistance.
Re: Regenerative Potential of Prostate Luminal Cells Revealed by Single-cell Analysis.
  • DOI:
    10.1016/j.eururo.2020.08.017
  • 发表时间:
    2021-01
  • 期刊:
  • 影响因子:
    23.4
  • 作者:
    Kyprianou N
  • 通讯作者:
    Kyprianou N
Pseudouridine as a novel biomarker in prostate cancer.
  • DOI:
    10.1016/j.urolonc.2020.06.026
  • 发表时间:
    2021-01
  • 期刊:
  • 影响因子:
    0
  • 作者:
    Stockert JA;Weil R;Yadav KK;Kyprianou N;Tewari AK
  • 通讯作者:
    Tewari AK
Molecular tracing of prostate cancer lethality.
  • DOI:
    10.1038/s41388-020-01496-5
  • 发表时间:
    2020-12
  • 期刊:
  • 影响因子:
    8
  • 作者:
    Wang YA;Sfakianos J;Tewari AK;Cordon-Cardo C;Kyprianou N
  • 通讯作者:
    Kyprianou N
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Natasha Kyprianou其他文献

Natasha Kyprianou的其他文献

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{{ truncateString('Natasha Kyprianou', 18)}}的其他基金

Treatment-Induced Phenotypic Reprogramming in Prostate Cancer
前列腺癌治疗诱导的表型重编程
  • 批准号:
    10113564
  • 财政年份:
    2019
  • 资助金额:
    $ 44.73万
  • 项目类别:
Treatment-Induced Phenotypic Reprogramming in Prostate Cancer
前列腺癌治疗诱导的表型重编程
  • 批准号:
    10022715
  • 财政年份:
    2019
  • 资助金额:
    $ 44.73万
  • 项目类别:
Treatment-Induced Phenotypic Reprogramming in Prostate Cancer
前列腺癌治疗诱导的表型重编程
  • 批准号:
    10348710
  • 财政年份:
    2019
  • 资助金额:
    $ 44.73万
  • 项目类别:
Treatment-Induced Phenotypic Reprogramming in Prostate Cancer
前列腺癌治疗诱导的表型重编程
  • 批准号:
    9763943
  • 财政年份:
    2019
  • 资助金额:
    $ 44.73万
  • 项目类别:
TGF-Beta Signaling Effectors in Prostate Growth Regulation/Tumor Progression
前列腺生长调节/肿瘤进展中的 TGF-β 信号传导效应器
  • 批准号:
    8527767
  • 财政年份:
    2010
  • 资助金额:
    $ 44.73万
  • 项目类别:
TGF-Beta Signaling Effectors in Prostate Growth Regulation/Tumor Progression
前列腺生长调节/肿瘤进展中的 TGF-β 信号传导效应器
  • 批准号:
    8129554
  • 财政年份:
    2010
  • 资助金额:
    $ 44.73万
  • 项目类别:
Novel Effectors of TGF-beta Signaling in Prostate Growth Regulation and Tumor Pro
前列腺生长调节和肿瘤 Pro 中 TGF-β 信号传导的新型效应器
  • 批准号:
    7996777
  • 财政年份:
    2010
  • 资助金额:
    $ 44.73万
  • 项目类别:
TGF-Beta Signaling Effectors in Prostate Growth Regulation/Tumor Progression
前列腺生长调节/肿瘤进展中的 TGF-β 信号传导效应器
  • 批准号:
    8322333
  • 财政年份:
    2010
  • 资助金额:
    $ 44.73万
  • 项目类别:
Anoikis Effect by Quinazolines on Prostate Growth
喹唑啉对前列腺生长的失巢效应
  • 批准号:
    6874451
  • 财政年份:
    2004
  • 资助金额:
    $ 44.73万
  • 项目类别:
Anoikis Effect by Quinazolines on Prostate Growth
喹唑啉对前列腺生长的失巢效应
  • 批准号:
    7414083
  • 财政年份:
    2004
  • 资助金额:
    $ 44.73万
  • 项目类别:

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