Role of alpha6 beta1 Integrin in Prostate Cancer

α6β1整合素在前列腺癌中的作用

基本信息

  • 批准号:
    8292638
  • 负责人:
  • 金额:
    $ 33.51万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2012
  • 资助国家:
    美国
  • 起止时间:
    2012-05-01 至 2017-03-31
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): The pathways that promote prostate cancer survival downstream of the androgen receptor (AR) remain unknown and that lack of knowledge is a critical barrier to the progress of treating prostate cancer. The goal of this proposal is to determine the mechanisms which promote prostate cancer survival in vivo and use this knowledge to test the feasibility of therapeutically targeting those survival pathways. Cell adhesion to extracellular matrix via integrins is critical for the survival of prostate cells. The mechanism by which integrin ¿6¿1is preferentially expressed in prostate cancer, to the virtual exclusion of other integrins, and the extent to which ¿6¿1controls cell survival in prostate tumors are not known. A new prostate cancer survival pathway in which AR directly controls ¿6¿1expression was recently identified and published. This pathway functions independently of the PI3K pathway, such that inhibition of both ¿6¿1and PI3K is required to effectively induce prostate cancer cell death. The objective of this proposal is to delineate the mechanisms by which the AR/ ¿6¿11 pathway drives prostate cancer survival and test the feasibility of using combined inhibition of ¿6¿1 and PI3K as a therapeutic approach. The hypothesis is that AR-dependent stimulation of integrin ¿6¿1 expression is required for NF?B /Bcl-xL/c-FLIP to promote survival of prostate cancer cells, and simultaneous inhibition of the ¿6¿1 and PI3K pathways is required to induce death of PI3K-dependent prostate cancer cells. In Aim 1, AR-expressing cell lines will be used to decipher the transcriptional and post-transcriptional mechanisms by which AR, Erg/Etv, and laminin-10 control integrin ¿6¿1 expression in prostate cancer. In Aim 2, AR-expressing cells will be used to delineate the specific signaling pathways downstream of AR/ ¿6¿1 that control prostate cancer survival. In Aim 3, human tissue and cell line xenografts will be used to test a new PI3K inhibitor, PX866, currently in phase I trials in combination with ¿6¿1 inhibition to suppress tumor survival and growth, and determine the contribution of integrin ¿6¿1 and PI3K to tumor survival in vivo. The proposed studies will significantly improve scientific knowledge in the fields of cell adhesion and survival signaling, b delineating the mechanistic basis behind a novel relationship between a nuclear hormone receptor and integrin ¿6¿1. Through these studies a more in-depth understanding of how steroids and integrins cooperate to control cell survival will be gained, which will further our knowledge of how the extracellular matrix impacts tumor cell survival. The prostate cancer field will be advanced by linking the prostate-specific Erg/Etv fusion oncogenes with a new AR/ ¿6¿1-dependent, but PI3K-independent, survival pathway that could be part of a strategy for treating prostate cancer patients. Assessment of this pathway in human patient xenografts will help to determine the feasibility of targeting these pathways in vivo and shift current paradigms by demonstrating the importance and contribution of AR to prostate tumor survival through the extracellular matrix. PUBLIC HEALTH RELEVANCE: Annually, prostate cancer is responsible for 29,000 deaths nationwide. How androgen promotes prostate tumor survival remains unknown, and that lack of knowledge is a critical barrier to progress in being able to treat prostate cancer. We identified a novel androgen-regulated prostate cancer cell survival pathway linking the prostate-specific Erg/Etv fusion oncogenes with integrin ¿6¿1-dependent survival, and are determining the feasibility of targeting this pathway as a strategy for treating prostate cancer patients to allevite their suffering.
描述(由申请人提供):促进雄激素受体(AR)下游前列腺癌生存的途径仍然未知,缺乏知识是前列腺癌治疗进展的关键障碍。该提案的目标是确定促进前列腺癌体内存活的机制,并使用这些知识来测试治疗靶向这些存活途径的可行性。细胞通过整合素粘附到细胞外基质对于前列腺细胞的存活至关重要。整合素<$6 <$1在前列腺癌中优先表达的机制,以及<$6 <$1在前列腺肿瘤中控制细胞存活的程度 不知道。最近发现并发表了一种新的前列腺癌生存途径,其中AR直接控制<$6 <$1表达。该途径独立于PI 3 K途径发挥作用,因此需要抑制<$6 <$1和PI 3 K来有效诱导前列腺癌细胞死亡。该提案的目的是描述AR/<$6 <$11通路驱动前列腺癌生存的机制,并测试使用<$6 <$1和PI 3 K的联合抑制作为治疗方法的可行性。该假说是,AR依赖性刺激整合素<$6 <$1的表达所需的NF?B /Bcl-xL/c-FLIP促进前列腺癌细胞的存活,并且需要同时抑制<$6 <$1和PI 3 K通路以诱导PI 3 K依赖性前列腺癌细胞的死亡。在目标1中,AR表达细胞系将用于破译AR、Erg/Etv和层粘连蛋白-10控制前列腺癌中整合素<$6 <$1表达的转录和转录后机制。在目标2中,AR表达细胞将用于描述控制前列腺癌生存的AR/6 <$1下游的特定信号通路。在目标3中,人类组织和细胞系异种移植物将用于测试一种新的PI 3 K抑制剂PX 866,目前在I期试验中与<$6 <$1抑制剂组合以抑制肿瘤存活和生长,并确定整合素<$6 <$1和PI 3 K对体内肿瘤存活的贡献。拟议的研究将显着提高科学知识领域的细胞粘附和生存信号,B描绘背后的一个新的关系核激素受体和整合素1的机制基础。通过这些研究,将获得对类固醇和整合素如何合作控制细胞存活的更深入的了解,这将进一步加深我们对细胞外基质如何影响肿瘤细胞存活的认识。前列腺癌领域将通过将前列腺特异性Erg/Etv融合癌基因与新的AR/6 1依赖性,但PI 3 K独立的生存途径联系起来来推进,这可能是治疗前列腺癌患者策略的一部分。在人类患者异种移植物中评估该途径将有助于确定体内靶向这些途径的可行性,并通过证明AR通过细胞外基质对前列腺肿瘤存活的重要性和贡献来改变当前的范式。 公共卫生相关性:每年,前列腺癌在全国造成29,000人死亡。雄激素如何促进前列腺肿瘤的生存仍然是未知的,缺乏知识是治疗前列腺癌的关键障碍。我们确定了一个 新的雄激素调节的前列腺癌细胞存活途径将前列腺特异性Erg/Etv融合癌基因与整合素6 1依赖性存活联系起来,并正在确定靶向该途径作为治疗前列腺癌患者以减轻其痛苦的策略的可行性。

项目成果

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Cynthia K Miranti其他文献

Cynthia K Miranti的其他文献

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{{ truncateString('Cynthia K Miranti', 18)}}的其他基金

Bioengineered Prostate-on Chip: Mechanisms of Stromal Dysregulation in Prostate Cancer
生物工程前列腺芯片:前列腺癌基质失调的机制
  • 批准号:
    10386865
  • 财政年份:
    2021
  • 资助金额:
    $ 33.51万
  • 项目类别:
Bioengineered Prostate-on Chip: Mechanisms of Stromal Dysregulation in Prostate Cancer
生物工程前列腺芯片:前列腺癌基质失调的机制
  • 批准号:
    10593937
  • 财政年份:
    2021
  • 资助金额:
    $ 33.51万
  • 项目类别:
Bioengineered Prostate-on Chip: Mechanisms of Stromal Dysregulation in Prostate Cancer
生物工程前列腺芯片:前列腺癌基质失调的机制
  • 批准号:
    10204253
  • 财政年份:
    2021
  • 资助金额:
    $ 33.51万
  • 项目类别:
Role of alpha6 beta1 Integrin in Prostate Cancer
α6β1整合素在前列腺癌中的作用
  • 批准号:
    8464670
  • 财政年份:
    2012
  • 资助金额:
    $ 33.51万
  • 项目类别:
Tyrosine Kinase Signaling in Cancer, Disease, & Development
癌症、疾病中的酪氨酸激酶信号传导,
  • 批准号:
    8398049
  • 财政年份:
    2012
  • 资助金额:
    $ 33.51万
  • 项目类别:
Role of alpha6 beta1 Integrin in Prostate Cancer
α6β1整合素在前列腺癌中的作用
  • 批准号:
    8665532
  • 财政年份:
    2012
  • 资助金额:
    $ 33.51万
  • 项目类别:
Role of alpha6 beta1 Integrin in Prostate Cancer
α6β1整合素在前列腺癌中的作用
  • 批准号:
    8627582
  • 财政年份:
    2012
  • 资助金额:
    $ 33.51万
  • 项目类别:
Role of alpha6 beta1 Integrin in Prostate Cancer
α6β1整合素在前列腺癌中的作用
  • 批准号:
    9024459
  • 财政年份:
    2012
  • 资助金额:
    $ 33.51万
  • 项目类别:
PROTEIN KINASE C AND INTEGRIN MEDIATED SIGNALING
蛋白激酶 C 和整合素介导的信号传导
  • 批准号:
    2769893
  • 财政年份:
    1998
  • 资助金额:
    $ 33.51万
  • 项目类别:
PROTEIN KINASE C AND INTEGRIN MEDIATED SIGNALING
蛋白激酶 C 和整合素介导的信号传导
  • 批准号:
    2115590
  • 财政年份:
    1997
  • 资助金额:
    $ 33.51万
  • 项目类别:

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