Magi2 in aggressive prostate cancer

Magi2 在侵袭性前列腺癌中的作用

基本信息

  • 批准号:
    9187439
  • 负责人:
  • 金额:
    $ 19.51万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2015
  • 资助国家:
    美国
  • 起止时间:
    2015-12-01 至 2018-11-30
  • 项目状态:
    已结题

项目摘要

 DESCRIPTION (provided by applicant): Most prostate cancers initially respond to androgen deprivation therapy but eventually progress to castration-resistant disease. Once castration-resistant prostate cancer (CRPC) arises, it cannot be effectively treated. This fact creates a need to better understand mechanisms of CRPC to enable new therapies for patients with advanced disease. In preliminary studies, we used transposon-based mutagenesis of androgen-sensitive prostate epithelial cells to derive sub-lines that were resistant to absence of androgens or the presence of bicalutamide. Molecular analysis of transposon insertions in the castration-resistant sub-lines identified MAGI2 as a potential driver of the castration resistant phenotype. Previous whole genome sequencing of human prostate cancers also found genomic rearrangements in MAGI2. Both the transposon insertions observed in our study and the rearrangements observed in human prostate cancers could potentially cause both loss of full-length MAGI2 expression and gain of expression for a truncated N-terminal fragment of MAGI2. Data mining the results of published RNA-seq studies of CRPC also identified candidate fusion transcripts involving the MAGI2 N-terminus. These data fit with additional preliminary studies of protein expression for the N-terminus of MAGI2 on human prostate cancer tissue microarrays. In these studies we observed that high expression of the MAGI2 N-terminus was associated with an increased risk of death from prostate cancer. In light of these findings, we hypothesize that over-expression of the N-terminus of MAGI2 drives progression to CRPC. We will test this hypothesis via gain- and loss-of-function approaches in cell line and mouse models (Aim 1) and by further investigating expression of the MAGI2 protein and candidate MAGI2-regulated pathways in human prostate cancer (Aim 2). This project will have high-impact outcomes for the effort to combat prostate cancer by furthering the goal of understanding mechanisms of resistance for men with prostate cancer. This project will also further the goal of distinguishing aggressive from indolent disease because our preliminary studies support the concept that MAGI2 and MAGI2-regulated pathways as potential biomarkers to distinguish aggressive from indolent disease.
 描述(申请人提供):大多数前列腺癌最初对雄激素剥夺治疗有反应,但最终进展为去势抵抗疾病。一旦出现去势抵抗型前列腺癌(CRPC),就无法有效治疗。这一事实需要更好地了解CRPC的机制,以便为晚期疾病患者提供新的治疗方法。在初步研究中,我们使用基于转座子的对雄激素敏感的前列腺上皮细胞的突变来获得耐受无雄激素的亚系。 或比卡鲁胺的存在。对抗去势亚系转座子插入的分子分析表明,MAGI2是抗去势表型的潜在驱动因素。之前对人类前列腺癌的全基因组测序也在MAGI2中发现了基因组重排。在我们的研究中观察到的转座子插入和在人类前列腺癌中观察到的重排都可能导致MAGI2全长表达的丧失和MAGI2 N末端片段的表达增加。数据挖掘发表的CRPC的RNA-seq研究结果也确定了涉及MAGI2 N末端的候选融合转录本。这些数据与人类前列腺癌组织微阵列上MAGI2 N-末端蛋白表达的其他初步研究相吻合。在这些研究中,我们观察到MAGI2N末端的高表达与前列腺癌死亡风险的增加有关。根据这些发现,我们假设MAGI2 N端的过度表达推动了向CRPC的进展。我们将通过在细胞系和小鼠模型中获得和失去功能的方法来验证这一假说(目标1),并通过进一步研究MAGI2蛋白和候选MAGI2调节的通路在人类前列腺癌中的表达(目标2)。该项目将通过进一步了解前列腺癌男性耐药机制的目标,对抗击前列腺癌的努力产生重大影响。该项目还将推动区分侵袭性和惰性疾病的目标,因为我们的初步研究支持MAGI2和MAGI2调节的通路作为区分侵袭性和惰性疾病的潜在生物标志物的概念。

项目成果

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Paul C Marker其他文献

Paul C Marker的其他文献

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{{ truncateString('Paul C Marker', 18)}}的其他基金

Growth hormone actions in prostate carcinogenesis
生长激素在前列腺癌发生中的作用
  • 批准号:
    10063500
  • 财政年份:
    2019
  • 资助金额:
    $ 19.51万
  • 项目类别:
Magi2 in aggressive prostate cancer
Magi2 在侵袭性前列腺癌中的作用
  • 批准号:
    9024983
  • 财政年份:
    2015
  • 资助金额:
    $ 19.51万
  • 项目类别:
Steroid hormones and SFRP1 in the age-related incidence of BPH and BOO
类固醇激素和 SFRP1 在与年龄相关的 BPH 和 BOO 发病率中的作用
  • 批准号:
    8328840
  • 财政年份:
    2011
  • 资助金额:
    $ 19.51万
  • 项目类别:
Steroid hormones and SFRP1 in the age-related incidence of BPH and BOO
类固醇激素和 SFRP1 在与年龄相关的 BPH 和 BOO 发病率中的作用
  • 批准号:
    8715776
  • 财政年份:
    2011
  • 资助金额:
    $ 19.51万
  • 项目类别:
Steroid hormones and SFRP1 in the age-related incidence of BPH and BOO
类固醇激素和 SFRP1 在与年龄相关的 BPH 和 BOO 发病率中的作用
  • 批准号:
    8528576
  • 财政年份:
    2011
  • 资助金额:
    $ 19.51万
  • 项目类别:
Steroid hormones and SFRP1 in the age-related incidence of BPH and BOO
类固醇激素和 SFRP1 在与年龄相关的 BPH 和 BOO 发病率中的作用
  • 批准号:
    8186950
  • 财政年份:
    2011
  • 资助金额:
    $ 19.51万
  • 项目类别:
Novel prostate cancer oncogenes identified by transposon mutagenesis
通过转座子诱变鉴定出新的前列腺癌癌基因
  • 批准号:
    8034799
  • 财政年份:
    2010
  • 资助金额:
    $ 19.51万
  • 项目类别:
Novel prostate cancer oncogenes identified by transposon mutagenesis
通过转座子诱变鉴定出新的前列腺癌癌基因
  • 批准号:
    8403838
  • 财政年份:
    2010
  • 资助金额:
    $ 19.51万
  • 项目类别:
Novel prostate cancer oncogenes identified by transposon mutagenesis
通过转座子诱变鉴定出新的前列腺癌癌基因
  • 批准号:
    7889176
  • 财政年份:
    2010
  • 资助金额:
    $ 19.51万
  • 项目类别:
Novel prostate cancer oncogenes identified by transposon mutagenesis
通过转座子诱变鉴定出新的前列腺癌癌基因
  • 批准号:
    8204600
  • 财政年份:
    2010
  • 资助金额:
    $ 19.51万
  • 项目类别:

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