Integrated Signaling in Pancreatic Cancer Progression

胰腺癌进展中的整合信号传导

基本信息

项目摘要

 DESCRIPTION (provided by applicant): Invasive pancreatic cancer (PDA) is a lethal disease. While certain genetic and epigenetic alterations have been well known for years, to date this has not resulted in useful preventive and/or therapeutic modalities. Our research goal is to identify driving alterations in gene expression that can be utilized to develop effective strategie to control PDA progression. Our previous studies have demonstrated that transcription factor FOXM1 is drastically increased in invasive PDA and this dysregulation critically promotes PDA biology, whereas PanINs do not exhibit substantially elevated FOXM1 expression. In sharp contrast, our recent study has shown a consistent lack of vitamin D receptor (VDR) expression in invasive PDA as compared to that in PanINs. Causally linking VDR loss to FOXM1 overexpression and functionally interrogating the underlying mechanisms are fundamentally important in understanding PDA progression. We postulate that downregulation of VDR expression causes FOXM1 overexpression and consequential acquisition of malignant phenotype in PDA, i.e., a switch from PanINs to invasive PDA. Therefore, activation and/or restoration of VDR signaling could attenuate PanINs progression and sensitize PDA to Vitamin D treatment. To test our hypothesis, we propose three specific aims: (1) Determine whether loss of VDR expression is a critical event of pancreatic cancer progression from PanIN to invasive PDA; (2) Determine the critical molecular mechanisms underlying dysregulation of VDR signaling in and its mechanistic impact on PDA progression; and (3) Determine whether an intact VDR signaling renders PanINs sensitive to Vitamin D treatment, while invasive PDA are refractory to Vitamin D due to loss of VDR expression. These three novel specific aims with clinical relevant question (aim 1), mechanistic substantiation (aim 2) and translational validation (aim 3), are supported by our respective preliminary data and can be tested independently using our unique research resources, yet they are highly interrelated and support one another. Our proposed studies will take advantage of the unique resources available at MD Anderson Cancer Center, including our large collection of pancreatic cancer specimens and mouse models. Given the important role of VDR/FOXM1 we have uncovered, we predict that completion of these studies will provide insightful information for the molecular basis of pancreatic cancer progression and for identification of molecular targets to design effective prevention and treatment strategies; and translation of our findings into benefiting PDA patients is our long term goal.
 描述(申请人提供):侵袭性胰腺癌(PDA)是一种致命的疾病。虽然某些遗传和表观遗传改变多年来已广为人知,但到目前为止,这还没有导致有效的预防和/或治疗方式。我们的研究目标是确定基因表达的驱动变化,这些变化可以用来开发有效的策略来控制PDA的进展。我们以前的研究已经证明,转录因子FOXM1在侵袭性PDA中显著增加,这种失衡关键地促进了PDA生物学,而Panins并没有显著增加FOXM1的表达。与此形成鲜明对比的是,我们最近的研究显示,与Panins相比,侵袭性PDA一直缺乏维生素D受体(VDR)的表达。将VDR缺失与FOXM1过度表达联系起来,并从功能上询问其潜在机制,对于理解PDA的进展是至关重要的。我们推测,VDR表达下调导致FOXM1过度表达,从而导致PDA恶性表型的获得,即从Panins转变为侵袭性PDA。因此,VDR信号的激活和/或恢复可以抑制Panins的进展,并使PDA对维生素D治疗敏感。为了验证我们的假设,我们提出了三个具体的目标:(1)确定VDR表达缺失是否是胰腺癌从Panin向侵袭性PDA进展的关键事件;(2)确定VDR信号失控的关键分子机制及其对PDA进展的机制影响;(3)确定完整的VDR信号使Panins对维生素D治疗敏感,而侵袭性PDA由于VDR表达缺失而对维生素D无效。这三个新的特定目标与临床相关问题(目标1)、机制证实(目标2)和翻译验证 (目标3),由我们各自的初步数据支持,并可利用我们独特的研究资源进行独立测试,但它们高度相关,相互支持。我们建议的研究将利用MD Anderson癌症中心提供的独特资源,包括我们收集的大量胰腺癌标本和小鼠模型。鉴于我们已经发现的vdr/foxm1的重要作用,我们预测这些研究的完成将为胰腺癌进展的分子基础和识别分子靶点以设计有效的预防和治疗策略提供有洞察力的信息;我们的发现转化为使pda患者受益是我们的长期目标。 进球。

项目成果

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ROBERT S BRESALIER其他文献

ROBERT S BRESALIER的其他文献

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{{ truncateString('ROBERT S BRESALIER', 18)}}的其他基金

Multi-cancer early detection using cell-free DNA methylome analysis
使用游离 DNA 甲基化分析进行多癌症早期检测
  • 批准号:
    10763305
  • 财政年份:
    2023
  • 资助金额:
    $ 36.6万
  • 项目类别:
Colorectal cancer risk factors, risk prediction and blood-based biomarker by tumor consensus molecular subtype
按肿瘤共有分子亚型分类的结直肠癌危险因素、风险预测和血液生物标志物
  • 批准号:
    10591999
  • 财政年份:
    2019
  • 资助金额:
    $ 36.6万
  • 项目类别:
Colorectal cancer risk factors, risk prediction and blood-based biomarker by tumor consensus molecular subtype
按肿瘤共有分子亚型分类的结直肠癌危险因素、风险预测和血液生物标志物
  • 批准号:
    10021547
  • 财政年份:
    2019
  • 资助金额:
    $ 36.6万
  • 项目类别:
Integrated Signaling in Pancreatic Cancer Progression
胰腺癌进展中的整合信号转导
  • 批准号:
    9493432
  • 财政年份:
    2016
  • 资助金额:
    $ 36.6万
  • 项目类别:
Integrated Signaling in Pancreatic Cancer Progression
胰腺癌进展中的整合信号转导
  • 批准号:
    10018467
  • 财政年份:
    2016
  • 资助金额:
    $ 36.6万
  • 项目类别:
Integrated Signaling in Pancreatic Cancer Progression
胰腺癌进展中的整合信号转导
  • 批准号:
    10247023
  • 财政年份:
    2016
  • 资助金额:
    $ 36.6万
  • 项目类别:
Molecular Mediators of Pancreatic Cancer Invasion and Progression
胰腺癌侵袭和进展的分子介质
  • 批准号:
    9250086
  • 财政年份:
    2013
  • 资助金额:
    $ 36.6万
  • 项目类别:
MUCIN GLYCOPROTEINS IN COLON CANCER METASTASIS
结肠癌转移中的粘蛋白糖蛋白
  • 批准号:
    6686311
  • 财政年份:
    2002
  • 资助金额:
    $ 36.6万
  • 项目类别:
Great Lakes New England Clinical Validation Center
新英格兰五大湖临床验证中心
  • 批准号:
    10484455
  • 财政年份:
    2000
  • 资助金额:
    $ 36.6万
  • 项目类别:
Great Lakes New England Clinical Validation Center
新英格兰五大湖临床验证中心
  • 批准号:
    10698103
  • 财政年份:
    2000
  • 资助金额:
    $ 36.6万
  • 项目类别:

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