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FoxM1: A molecular target in pancreatic cancer

FoxM1：胰腺癌的分子靶点

基本信息

批准号：
8206713
负责人：
FAZLUL H. SARKAR
金额：
$ 30.59万
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/8206713
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 Health Human In Vitro Induction of Apoptosis Inflammation Laboratories 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 cancer cells pancreatic neoplasm prevent 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）：