FoxM1: A molecular target in pancreatic cancer

FoxM1：胰腺癌的分子靶点

• 批准号: 7577258
• 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
• 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/7577258
• 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

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）是一种侵略性恶性肿瘤，是所有癌症中最糟糕的结果之一。这可能部分是由于PC细胞在疾病早期过程中迁移，入侵，血管生成和转移过程中的“转动开关”进行编排的能力。因此，迫切需要开发新的策略，可以防止胰腺肿瘤进展。已知在PC中通常看到的EGFR和AKT信号传导的组成型激活会激活NF-：B，它在转录上调节了许多有助于侵袭性肿瘤生长，血管生成和浸润的基因，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中激活，并且似乎与NF-：B串扰（请参阅我们的初步结果）。但是，尚未完全了解FOXM1和Notch-1与NF-：B的串扰并调节其下游基因。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的调节，这有助于抑制细胞生长，诱导凋亡以及抑制肿瘤细胞侵袭和血管生成。根据我们的初步数据以及由于对FOXM1，Notch-1和Nf-：B信号之间的调节和串扰缺乏分子的理解，我们假设我们假设FOXM1，Notch-1和Nf-和Nf-和Nf-和Nf-：B之间对分子串扰的进一步理解是为了设计有效的策略方法，可以更好地设计策略。我们将通过实现以下特定目标来检验我们的假设。我们将（i）确定FOXM1和NOTCH-1与NF-：B的串扰并调节其下游基因，并确定FOXM1/Notch-1/Nf-：B的后果在PC细胞生长，凋亡，肿瘤细胞侵袭和血管生成中的下降结果。接下来，（ii）我们将测试我们的新方法（例如使用染料木黄酮）对FOXM1/NOTCH-1信号的下调是否不仅可以抑制侵袭并促进凋亡细胞死亡，而且还可以使PC细胞对EGFR-酪氨酸激酶抑制剂（Erlotinib）（Erlotinib）和吉氏蛋白替替替替替汀诱导的杀戮杀害。我们还将测试染料木黄酮的化学敏化作用是否与FOXM1/Notch-1/Nf-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的转基因小鼠模型）通过测试（a）染料蛋白酶是否降低FOXM1/Notch-1/nf-的调节是否可以使PC细胞对PC细胞敏感，并且可以使PC细胞敏感，并且可以启用粉状素的刺激（B），并且对（notch）的降落剂量是否可以敏感（by），以降低染料剂和象征性的（thumor）诱导的（by）是否敏感（notch），并且是象征性象征的（B）是否敏感（by），仿制降低了仿生的调节（a），以降低染料蛋白酶的调节（a），（a）与动物肿瘤组织中FOXM1/Notch-1/nf-的下降调节相关。我们的研究结果将有助于设计一种新颖的针对性方法，以预防肿瘤进展，这将与一般的公共卫生高度相关，尤其是挽救被诊断出患有这种致命疾病的患者的生命。公共卫生相关性：该项目的重点是阐明化学预防剂可以防止胰腺肿瘤进展的机制。因此，该赠款与预防胃肠道恶性肿瘤有关。我们假设染料木黄酮会下调FOXM1和Notch-1信号传导，而Notch-1信号传导又下调了NF-：B及其下游基因，从而抑制了肿瘤进展。我们将使用体外分子方法和体内动物模型（Orthotopic小鼠模型和PC的转基因小鼠模型），通过三个特定目标来检验我们的假设。