IKK/NF-kappaB Signaling in Cancer: Therapy, Resistance, and Tumor Initiating Cells

癌症中的 IKK/NF-kappaB 信号传导:治疗、耐药性和肿瘤起始细胞

基本信息

项目摘要

 DESCRIPTION (provided by applicant): The IKK/NF-B pathway is clearly important in cancer initiation and progression, yet we do not fully understand the mechanisms whereby this pathway promotes the oncogenic phenotype and there are no specific inhibitors in the clinic. Complexity in cancer relative to NF-B is raised by recent findings that both canonical and non- canonical NF-B contribute to cancer progression, yet many studies only focus on the canonical pathway and then conclude that NF-B is important in a particular cancer but not absolutely critical. Additionally, complexity is raised by results demonstrating that IKK has critical signaling functions separate from its ability to regulate NF-B; for example we have found that IKK controls autophagy and mTORC1 signaling, both important in many cancers - yet thought to be mutually antagonistic. Recently we and others have established a role for IKK/NF-B signaling in promoting the triple-negative breast cancer tumor initiating cell (TIC) phenotype, with evidence that both canonical and non-canonical IKK/NF-B are important. Additionally, preliminary data in prostate cancer and glioma shows that IKK/NF-B signaling is critical for the TIC phenotype. In all of these studies, NF-B activity is enhanced/ altered in te TIC compartment, although a mechanism to explain this is not known. Preliminary data indicate a divergent IKK/NF-B mechanism in PSA-low/AR-low and PSA-high/AR- high prostate cancer cells and indicates the involvement of IKK in promoting reduced AR levels in the prostate TICs, potentially by direct phosphorylation. The PSA-low/AR-low prostate TICs are resistant to anti-AR therapy, suggesting that recurrence of prostate cancer is driven by survival/expansion of this cell compartment. Goals of this proposal are to: (i) characterize distinct contributions of canonical and non-canonical NF-B on Ras-driven cancer and on breast cancer, (ii) identify transcriptional output related to canonical and non- canonical NF-B in cancer, (iii) determine the involvement of NF-B signaling in driving the tumor-initiating cell phenotype - focused on brain, glioma, and prostate cancer, with additional studies related the involvement of the IKKpathway in promoting the PSA-lo/AR-lo TIC phenotype with the hypothesis that this drives resistance to anti-AR therapies, (iv) determine signaling events that promote an altered NF-B response in TICs, (v) characterize the IKK signaling network, relating IKK signaling to control of autophagy and mTORC1 signaling in cancers, with the hypothesis that IKK functions drives both pathways to be active, (vi) determine mechanisms of resistance to IKK inhibitors - focused on compensation by remaining IKK/NF-B signaling, and by kinome reprogramming and (vii) to facilitate movement of inhibitors into pre-clinical and clinical settings.
 描述(申请人提供):IKK/NF-κ B B通路在癌症的发生和发展中显然是重要的,但我们并不完全了解该通路促进致癌表型的机制,临床上也没有特异性抑制剂。最近的发现提高了癌症中与NF-κ B B相关的复杂性,即经典和非经典NF-κ B B都有助于癌症进展,然而许多研究仅关注经典途径,然后得出结论NF-κ B B在特定癌症中是重要的,但不是绝对关键的.此外,证明IKK具有与其调节NF-κ B B的能力分开的关键信号传导功能的结果增加了复杂性;例如,我们发现IKK控制自噬和mTORC 1信号传导,这两者在许多癌症中都很重要,但被认为是相互拮抗的。最近,我们和其他人已经确定了IKK/NF-κ B B信号在促进三阴性乳腺癌肿瘤起始细胞(TIC)表型中的作用,有证据表明经典和非经典IKK/NF-κ B B都很重要。此外,前列腺癌和神经胶质瘤的初步数据显示IKK/NF-κ B B信号传导对TIC表型至关重要.在所有这些研究中,NF-κ B B活性在TIC隔室中增强/改变,尽管解释这一现象的机制尚不清楚.初步数据表明,在PSA-低/AR-低和PSA-高/AR-高前列腺癌细胞中存在不同的IKK/NF-κ B B机制,并表明IKK κ B可能通过直接磷酸化参与促进前列腺TIC中AR水平降低。PSA-低/AR-低前列腺TIC对抗AR疗法具有抗性,表明前列腺癌的复发是由该细胞区室的存活/扩增驱动的。本提案的目标是:㈠确定 典型和非典型NF-κ B B对Ras驱动的癌症和乳腺癌的影响,(ii)鉴定癌症中与典型和非典型NF-κ B B相关的转录输出,(iii)确定NF-κ B B信号传导参与驱动肿瘤起始细胞表型-集中于脑、神经胶质瘤和前列腺癌,其他研究将IKK途径参与促进PSA-lo/AR-lo TIC表型与假设这会导致对抗AR疗法的耐药性相关,(iv)确定促进TIC中改变的NF-κ B B应答的信号传导事件,(v)表征IKK信号传导网络,将IKK信号传导与癌症中的自噬和mTORC 1信号传导的控制相关联,假设IKK功能驱动两种途径活化,(vi)确定对IKK抑制剂的抗性机制-集中于通过剩余IKK/NF-κ B B信号传导和通过激酶组重编程的补偿,和(vii)促进抑制剂进入临床前和临床环境。

项目成果

期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ monograph.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ sciAawards.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ conferencePapers.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ patent.updateTime }}

ALBERT Sidney BALDWIN其他文献

ALBERT Sidney BALDWIN的其他文献

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

{{ truncateString('ALBERT Sidney BALDWIN', 18)}}的其他基金

SToP Cancer SPORE: Developmental Research Program
STOP Cancer SPORE:发展研究计划
  • 批准号:
    10705611
  • 财政年份:
    2022
  • 资助金额:
    $ 84.83万
  • 项目类别:
SToP Cancer SPORE: Developmental Research Program
STOP Cancer SPORE:发展研究计划
  • 批准号:
    10334088
  • 财政年份:
    2022
  • 资助金额:
    $ 84.83万
  • 项目类别:
A consortium effort to translate therapies for neurological diseases via an ex vivo organotypic platform
一个联盟致力于通过离体器官平台转化神经系统疾病的疗法
  • 批准号:
    10436954
  • 财政年份:
    2021
  • 资助金额:
    $ 84.83万
  • 项目类别:
A consortium effort to translate therapies for neurological diseases via an ex vivo organotypic platform
一个联盟致力于通过离体器官平台转化神经系统疾病的疗法
  • 批准号:
    10214893
  • 财政年份:
    2021
  • 资助金额:
    $ 84.83万
  • 项目类别:
A consortium effort to translate therapies for neurological diseases via an ex vivo organotypic platform
一个联盟致力于通过离体器官平台转化神经系统疾病的疗法
  • 批准号:
    10655357
  • 财政年份:
    2021
  • 资助金额:
    $ 84.83万
  • 项目类别:
IKK/NF-kappaB Signaling in Cancer: Therapy, Resistance, and Tumor Initiating Cells
癌症中的 IKK/NF-kappaB 信号传导:治疗、耐药性和肿瘤起始细胞
  • 批准号:
    9214322
  • 财政年份:
    2016
  • 资助金额:
    $ 84.83万
  • 项目类别:
IKK/NF-kappaB Signaling in Cancer: Therapy, Resistance, and Tumor Initiating Cells
癌症中的 IKK/NF-kappaB 信号传导:治疗、耐药性和肿瘤起始细胞
  • 批准号:
    10330374
  • 财政年份:
    2016
  • 资助金额:
    $ 84.83万
  • 项目类别:
Function and Mechanism of TET Regulation of Tumor Immunity
TET调节肿瘤免疫的功能及机制
  • 批准号:
    10689090
  • 财政年份:
    2012
  • 资助金额:
    $ 84.83万
  • 项目类别:
Function and Mechanism of TET Regulation of Tumor Immunity
TET调节肿瘤免疫的功能及机制
  • 批准号:
    10020932
  • 财政年份:
    2012
  • 资助金额:
    $ 84.83万
  • 项目类别:
Regulation of Basal-Like and Her2+ Breast Cancer Phenotypes by IKK/NF-kappaB
IKK/NF-kappaB 对 Basal-Like 和 Her2 乳腺癌表型的调节
  • 批准号:
    8205037
  • 财政年份:
    2010
  • 资助金额:
    $ 84.83万
  • 项目类别:

相似海外基金

The earliest exploration of land by animals: from trace fossils to numerical analyses
动物对陆地的最早探索:从痕迹化石到数值分析
  • 批准号:
    EP/Z000920/1
  • 财政年份:
    2025
  • 资助金额:
    $ 84.83万
  • 项目类别:
    Fellowship
Animals and geopolitics in South Asian borderlands
南亚边境地区的动物和地缘政治
  • 批准号:
    FT230100276
  • 财政年份:
    2024
  • 资助金额:
    $ 84.83万
  • 项目类别:
    ARC Future Fellowships
The function of the RNA methylome in animals
RNA甲基化组在动物中的功能
  • 批准号:
    MR/X024261/1
  • 财政年份:
    2024
  • 资助金额:
    $ 84.83万
  • 项目类别:
    Fellowship
Ecological and phylogenomic insights into infectious diseases in animals
对动物传染病的生态学和系统发育学见解
  • 批准号:
    DE240100388
  • 财政年份:
    2024
  • 资助金额:
    $ 84.83万
  • 项目类别:
    Discovery Early Career Researcher Award
Zootropolis: Multi-species archaeological, ecological and historical approaches to animals in Medieval urban Scotland
Zootropolis:苏格兰中世纪城市动物的多物种考古、生态和历史方法
  • 批准号:
    2889694
  • 财政年份:
    2023
  • 资助金额:
    $ 84.83万
  • 项目类别:
    Studentship
Using novel modelling approaches to investigate the evolution of symmetry in early animals.
使用新颖的建模方法来研究早期动物的对称性进化。
  • 批准号:
    2842926
  • 财政年份:
    2023
  • 资助金额:
    $ 84.83万
  • 项目类别:
    Studentship
Study of human late fetal lung tissue and 3D in vitro organoids to replace and reduce animals in lung developmental research
研究人类晚期胎儿肺组织和 3D 体外类器官在肺发育研究中替代和减少动物
  • 批准号:
    NC/X001644/1
  • 财政年份:
    2023
  • 资助金额:
    $ 84.83万
  • 项目类别:
    Training Grant
RUI: Unilateral Lasing in Underwater Animals
RUI:水下动物的单侧激光攻击
  • 批准号:
    2337595
  • 财政年份:
    2023
  • 资助金额:
    $ 84.83万
  • 项目类别:
    Continuing Grant
RUI:OSIB:The effects of high disease risk on uninfected animals
RUI:OSIB:高疾病风险对未感染动物的影响
  • 批准号:
    2232190
  • 财政年份:
    2023
  • 资助金额:
    $ 84.83万
  • 项目类别:
    Continuing Grant
A method for identifying taxonomy of plants and animals in metagenomic samples
一种识别宏基因组样本中植物和动物分类的方法
  • 批准号:
    23K17514
  • 财政年份:
    2023
  • 资助金额:
    $ 84.83万
  • 项目类别:
    Grant-in-Aid for Challenging Research (Exploratory)
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了