Integrated Signaling in Pancreatic Cancer Progression

胰腺癌进展中的整合信号传导

基本信息

批准号：
9266771
负责人：
ROBERT S BRESALIER
金额：
$ 36.6万
依托单位：
UNIVERSITY OF TX MD ANDERSON CAN CTR
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-05-01 至 2021-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9266771
关键词：
Ablation Attenuated Automobile Driving Cancer Biology Cancer Center Cancer Patient Collection Complement Consequentialism Data Development Disease Down-Regulation Epigenetic Process Evaluation Event FOXM1 gene Gene Expression Genetic Goals Homeostasis Human In Vitro Incidence Lesion Link Malignant neoplasm of pancreas Mediating Modality Modeling Molecular Molecular Target Mus Pancreas Pancreatic Intraepithelial Neoplasia Pathologic Pathway interactions Premalignant Prevention strategy Preventive Proteins Receptor Signaling Refractory Regulation Research Resistance Resources Role Signal Transduction Specimen Testing Therapeutic Therapeutic Effect Tissues Translations Validation Vitamin D Vitamin D3 Receptor clinically relevant design effective intervention genetic manipulation in vivo Model malignant phenotype mouse model novel overexpression pancreatic cancer cells public health relevance receptor downregulation receptor expression receptor function response restoration transcription factor treatment strategy tumor progression

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（由申请人提供）：侵袭性胰腺癌（PDA）是一种致命疾病，虽然某些遗传和表观遗传改变已众所周知，但迄今为止，这尚未产生有用的预防和/或治疗方式。我们之前的研究表明，转录因子 FOXM1 在侵袭性 PDA 中显着增加，并且这种失调严重促进了 PDA 的发展。 PDA 生物学，而 PanIN 并未表现出大幅升高的 FOXM1 表达，与此形成鲜明对比的是，我们最近的研究表明，与 PanIN 相比，侵入性 PDA 中始终缺乏维生素 D 受体 (VDR) 表达，这与 VDR 缺失与 FOXM1 过度表达存在因果关系。我们推测 VDR 表达下调会导致 FOXM1 过度表达，从而导致恶性表型的获得。 PDA，即从 PanINs 到侵入性 PDA 的转变，因此，VDR 信号传导的激活和/或恢复可以减弱 PanINs 的进展并使 PDA 对维生素 D 治疗敏感。 VDR 表达缺失是胰腺癌从 PanIN 进展为侵袭性 PDA 的关键事件 (2) 确定 VDR 信号传导失调的关键分子机制及其机制； (3) 确定完整的 VDR 信号传导是否使 PanIN 对维生素 D 治疗敏感，而侵入性 PDA 由于 VDR 表达缺失而对维生素 D 无效。这三个具有临床相关问题的新的具体目标（目标 1）。）、机械证实（目标 2）和翻译验证（目标 3）得到我们各自的初步数据的支持，并且可以使用我们独特的研究资源进行独立测试，但它们高度相关并相互支持，我们提出的研究将利用 MD 安德森癌症中心提供的独特资源，鉴于我们发现的 VDR/FOXM1 的重要作用，包括我们收集的大量胰腺癌标本和小鼠模型，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提供深入的信息。设计有效的预防和治疗策略；将我们的研究结果转化为造福 PDA 患者是我们的长期目标目标。