FoxM1: A molecular target in pancreatic cancer

FoxM1：胰腺癌的分子靶点

基本信息

批准号：
7749993
负责人：
FAZLUL H. SARKAR
金额：
$ 31.54万
依托单位：
WAYNE STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-01-01 至 2013-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7749993
关键词：
Animal Model Animals Antibodies Apoptosis Apoptotic Cancer Cell Growth Cancer Etiology Cancer Patient Cell Death Cell Death Inhibition Cell Survival Cessation of life Chemoprevention Chemopreventive Agent Cisplatin Combined Modality Therapy Complex Cytoplasm Data Development Diagnosis Disease Down-Regulation Epidermal Growth Factor Receptor Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Erlotinib Etiology Gelatinase B Gene Targeting Genes Genistein Goals Grant Growth Human In Vitro Induction of Apoptosis Inflammation Laboratories Life Malignant Neoplasms Malignant neoplasm of pancreas Mediating Methods Molecular Molecular Target Mus Neoplasm Metastasis Newly Diagnosed Notch Signaling Pathway Outcome Paclitaxel Pathogenesis Pathway interactions Patients Prevention Prevention approach Prevention strategy Preventive Process Public Health Publishing Radiation Radiation therapy Radio Receptor Activation Receptor Signaling Recurrence Regulation Reporting Research Resected Resistance Role Signal Pathway Signal Transduction Signaling Molecule Small Interfering RNA Solid Neoplasm Techniques Testing Therapeutic Therapeutic Agents Time Topotecan Transgenic Animals Transgenic Mice Tumor Angiogenesis Tumor Cell Invasion Tumor Tissue United States Vascular Endothelial Growth Factors Work Xenograft Model advanced disease angiogenesis base cancer cell cell growth chemotherapeutic agent design fighting gastrointestinal gemcitabine in vivo inhibitor/antagonist interest killings metastatic process migration mortality mouse model neoplastic neoplastic cell notch protein novel novel strategies novel therapeutic intervention outcome forecast palliative pancreatic neoplasm prevent public health relevance research study response soy protein isolate therapeutic target transcription factor tumor tumor growth tumor progression tumorigenesis wortmannin

项目摘要

DESCRIPTION (provided by applicant): Pancreatic cancer (PC) is an aggressive malignancy with one of the worst outcomes among all cancers. This could be partly due to the ability of PC cells to orchestrate in "turning-on the switch" for migration, invasion, angiogenesis and metastatic processes during the early course of the disease. Therefore, there is a dire need for the development of novel strategies by which pancreatic tumor progression could be prevented. The constitutive activation of EGFR and Akt signaling, commonly seen in PC, is known to activate NF-:B, which transcriptionally regulates many genes contributing to aggressive tumor growth, angiogenesis and invasion, resulting in tumor progression. Moreover, recent studies have shown that the FoxM1 and Notch-1 signaling pathways are also activated in PC and appear to crosstalk with NF-:B (please see our preliminary results). However, how FoxM1 and Notch-1 crosstalk with NF-:B and regulate their downstream genes are not fully understood. Our preliminary data clearly suggest that the inactivation of FoxM1 and Notch-1 signaling causes down regulation of NF-:B, which contribute to the inhibition of cell growth, induction of apoptosis and inhibition of tumor cell invasion and angiogenesis. Based on our preliminary data and because of the lack of molecular understanding of the regulation and crosstalk between FoxM1, Notch-1 and NF-:B signaling, we hypothesize that further understanding of the molecular crosstalk between FoxM1, Notch- 1 and NF-:B, and their down-regulation by a novel agent could be an effective approach for designing better strategies for the prevention of pancreatic tumor progression. We will test our hypothesis by accomplishing the following specific aims. We will (i) determine how FoxM1 and Notch-1 crosstalk with NF-:B and regulates their downstream genes, and determine the consequence of down regulation of FoxM1/Notch- 1/NF-:B in PC cell growth, apoptosis, tumor cell invasion and angiogenesis. Next, (ii) we will test whether the down regulation of FoxM1/Notch-1 signaling by our novel approach (such as the use of genistein) could not only inhibit invasion and promote apoptotic cell death but also sensitize PC cells to an EGFR-tyrosine kinase inhibitor (erlotinib) and gemcitabine-induced killing. We will also test whether the chemo-sensitizing effect of genistein is mechanistically associated with the down regulation of FoxM1/Notch-1/NF-:B signaling. Finally, (iii) we will conduct in vivo experiments (using both orthotopic mouse model and transgenic mouse models of PC) to recapitulate our in vitro findings by testing (a) whether genistein-induced down regulation of FoxM1/Notch-1/NF-:B signaling could sensitize PC cells to erlotinib and gemcitabine induced killing, and (b) whether the inhibition of tumor progression could correlate with the down regulation of FoxM1/Notch-1/NF-:B signaling in animal tumor tissues. The results of our research will aid in designing a novel and targeted approach for the prevention of tumor progression, which would be highly relevant to public health in general and especially for saving lives of patients diagnosed with this deadly disease. PUBLIC HEALTH RELEVANCE: This project is focused on elucidating the mechanism by which a chemopreventive agent could prevent pancreatic tumor progression. Therefore, this grant is related to the prevention of gastrointestinal malignancy. We hypothesize that genistein down-regulates FoxM1 and Notch-1 signaling, which in turn down-regulate NF-:B and its downstream genes, resulting in the inhibition of tumor progression. We will test our hypothesis by three specific aims using molecular approaches in vitro and by using animal models in vivo (both orthotopic mouse model and transgenic mouse models of PC).

描述（由申请人提供）：胰腺癌（PC）是一种侵袭性恶性肿瘤，是所有癌症中预后最差的一种。这可能部分归因于PC细胞在疾病早期过程中协调“打开开关”以进行迁移、侵袭、血管生成和转移过程的能力。因此，迫切需要开发新的策略来预防胰腺肿瘤的进展。 PC 中常见的 EGFR 和 Akt 信号传导的组成型激活会激活 NF-:B，后者在转录上调节许多基因，促进肿瘤的侵袭性生长、血管生成和侵袭，从而导致肿瘤进展。此外，最近的研究表明，FoxM1 和 Notch-1 信号通路也在 PC 中被激活，并且似乎与 NF-:B 串扰（请参阅我们的初步结果）。然而，FoxM1 和 Notch-1 如何与 NF-:B 相互作用并调节其下游基因尚不完全清楚。我们的初步数据清楚地表明，FoxM1 和 Notch-1 信号传导失活会导致 NF-:B 下调，从而有助于抑制细胞生长、诱导细胞凋亡以及抑制肿瘤细胞侵袭和血管生成。基于我们的初步数据，由于缺乏对 FoxM1、Notch-1 和 NF-:B 信号传导之间的分子串扰的分子理解，我们假设进一步了解 FoxM1、Notch-1 和 NF-之间的分子串扰： B，以及通过新药物下调它们可能是设计更好的预防胰腺肿瘤进展策略的有效方法。我们将通过实现以下具体目标来检验我们的假设。我们将 (i) 确定 FoxM1 和 Notch-1 如何与 NF-:B 串扰并调节其下游基因，并确定 FoxM1/Notch-1/NF-:B 下调对 PC 细胞生长、凋亡、肿瘤的影响细胞侵袭和血管生成。接下来，（ii）我们将测试通过我们的新方法（例如使用金雀异黄素）下调 FoxM1/Notch-1 信号传导是否不仅可以抑制侵袭并促进细胞凋亡，而且还可以使 PC 细胞对 EGFR- 敏感。酪氨酸激酶抑制剂（厄洛替尼）和吉西他滨诱导的杀伤作用。我们还将测试金雀异黄素的化疗增敏作用是否在机制上与 FoxM1/Notch-1/NF-:B 信号传导的下调相关。最后，(iii) 我们将进行体内实验（使用原位小鼠模型和 PC 转基因小鼠模型），通过测试 (a) 金雀异黄素是否诱导 FoxM1/Notch-1/NF- 的下调来概括我们的体外发现。 :B 信号传导可使 PC 细胞对厄洛替尼和吉西他滨诱导的杀伤敏感，以及 (b) 肿瘤进展的抑制是否与 FoxM1/Notch-1/NF-:B 的下调相关动物肿瘤组织中的信号传导。我们的研究结果将有助于设计一种新颖且有针对性的方法来预防肿瘤进展，这与一般公众健康高度相关，特别是对于挽救被诊断患有这种致命疾病的患者的生命。公共健康相关性：该项目的重点是阐明化学预防剂预防胰腺肿瘤进展的机制。因此，这笔资助与预防胃肠道恶性肿瘤有关。我们假设金雀异黄素下调 FoxM1 和 Notch-1 信号传导，进而下调 NF-:B 及其下游基因，从而抑制肿瘤进展。我们将使用体外分子方法和体内动物模型（原位小鼠模型和 PC 转基因小鼠模型）通过三个具体目标来检验我们的假设。