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:
    9024459
  • 负责人:
  • 金额:
    $ 3.45万
  • 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 2016-08-31
  • 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 α6ß1 is preferentially expressed in prostate cancer, to the virtual exclusion of other integrins, and the extent to which α6ß1controls cell survival in prostate tumors are not known. A new prostate cancer survival pathway in which AR directly controls α6ß1 expression was recently identified and published. This pathway functions independently of the PI3K pathway, such that inhibition of both α6ß1 and PI3K is required to effectively induce prostate cancer cell death. The objective of this proposal is to delineate the mechanisms by which the AR/α6ß1 pathway drives prostate cancer survival and test the feasibility of using combined inhibition of α6ß1 and PI3K as a therapeutic approach. The hypothesis is that AR-dependent stimulation of integrin α6ß1 expression is required for NFκB /Bcl-xL/c-FLIP to promote survival of prostate cancer cells, and simultaneous inhibition of the α6ß1 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 α6ß1 expression in prostate cancer. In Aim 2, AR-expressing cells will be used to delineate the specific signaling pathways downstream of AR/α6ß1 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 α6ß1 inhibition to suppress tumor survival and growth, and determine the contribution of integrin α6ß1 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 α6ß1. 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/α6ß1-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.
描述(由申请人提供):雄激素受体(AR)下游促进前列腺癌存活的途径仍然未知,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,并利用这些知识来测试针对这些存活途径进行治疗的可行性。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 α6ß1 在前列腺癌中优先表达、几乎排除其他整合素的机制,以及 α6ß1 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 α6ß1 表达。该通路的功能独立于 PI3K 通路,因此需要同时抑制 α6ß1 和 PI3K 才能有效诱导前列腺癌细胞死亡。该提案的目的是描述 AR/α6ß1 通路驱动前列腺癌存活的机制,并测试联合抑制 α6ß1 和 PI3K 作为治疗方法的可行性。该假设认为,NFκB /Bcl-xL/c-FLIP 需要 AR 依赖性刺激整合素 α6ß1 表达来促进前列腺癌细胞的存活,并且需要同时抑制 α6ß1 和 PI3K 途径来诱导 PI3K 依赖性前列腺癌细胞死亡。在目标 1 中,表达 AR 的细胞系将用于破译 AR、Erg/Etv 和 laminin-10 控制前列腺癌中整合素 α6ß1 表达的转录和转录后机制。在目标 2 中,表达 AR 的细胞将用于描绘 AR 下游的特定信号传导途径。 AR/α6ß1 控制前列腺癌的存活。在目标 3 中,人体组织和细胞系异种移植物将用于测试一种新的 PI3K 抑制剂 PX866,该抑制剂目前处于 I 期试验中,与 α6ß1 抑制剂联合使用以抑制肿瘤存活和生长,并确定整合素 α6ß1 和 PI3K 对体内肿瘤存活的贡献。拟议的研究将显着提高细胞粘附和生存信号领域的科学知识,b 描绘核激素受体和整合素 α6ß1 之间新关系背后的机制基础。通过这些研究,将更深入地了解类固醇和整合素如何合作控制细胞存活,这将进一步了解细胞外基质如何​​影响肿瘤细胞存活。通过将前列腺特异性 Erg/Etv 融合癌基因与新的 AR/α6ß1 依赖但不依赖 PI3K 的生存途径联系起来,前列腺癌领域将得到推进,该途径可能成为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这一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。

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:
    $ 3.45万
  • 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:
    $ 3.45万
  • 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:
    $ 3.45万
  • 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:
    $ 3.45万
  • 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:
    8292638
  • 财政年份:
    2012
  • 资助金额:
    $ 3.45万
  • 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:
    $ 3.45万
  • 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:
    $ 3.45万
  • 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:
    $ 3.45万
  • 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:
    $ 3.45万
  • 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:
    $ 3.45万
  • 项目类别:

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