FoxM1: A molecular target in pancreatic cancer

FoxM1：胰腺癌的分子靶点

• 批准号: 8408826
• 负责人: FAZLUL H. SARKAR
• 金额: $ 28.76万
• 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 2014-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8408826
• 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; Radioresistance; 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

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.

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癌症之一。这可能部分是由于PC细胞在疾病早期过程中协调迁移、侵袭、血管生成和转移过程的“打开开关”的能力。因此，迫切需要开发新的策略，通过该策略可以预防胰腺肿瘤进展。EGFR和Akt信号传导的组成性激活（通常见于PC）已知激活NF-：B，NF-：B转录调节许多有助于侵袭性肿瘤生长、血管生成和侵袭的基因，导致肿瘤进展。此外，最近的研究表明，FoxM 1和Notch-1信号通路也在PC中被激活，并且似乎与NF-：B发生串扰（请参见我们的初步结果）。然而，FoxM 1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，FoxM 1和Notch-1信号转导的失活导致NF-：B的下调，这有助于抑制细胞生长，诱导凋亡和抑制肿瘤细胞侵袭和血管生成。基于我们的初步数据，并且由于缺乏对FoxM 1、Notch-1和NF-：B信号传导之间的调节和串扰的分子理解，我们假设，进一步理解FoxM 1、Notch- 1和NF-：B之间的分子串扰，以及通过新试剂下调它们，可能是设计更好的预防胰腺肿瘤进展的策略的有效方法。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FoxM 1和Notch-1如何与NF-：B相互作用并调节其下游基因，并确定FoxM 1/Notch- 1/NF-：B下调在PC细胞生长、凋亡、肿瘤细胞侵袭和血管生成中的后果。接下来，（ii）我们将测试通过我们的新方法（例如使用染料木黄酮）下调FoxM 1/Notch-1信号传导是否不仅可以抑制侵袭和促进凋亡细胞死亡，而且还可以使PC细胞对EGFR-酪氨酸激酶抑制剂（厄洛替尼）和吉西他滨诱导的杀伤敏感。我们还将测试染料木黄酮的化学增敏作用是否与FoxM 1/Notch-1/NF-：B信号转导的下调机制相关。最后，（iii）我们将进行体内实验（使用PC的原位小鼠模型和转基因小鼠模型），通过测试（a）染料木素诱导的FoxM 1/Notch-1/NF-：B信号转导的下调是否可以使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可以与动物肿瘤组织中FoxM 1/Notch-1/NF-：B信号转导的下调相关，来概括我们的体外发现。我们的研究结果将有助于设计一种新的、有针对性的方法来预防肿瘤进展，这将与一般公共卫生高度相关，特别是对于挽救被诊断患有这种致命疾病的患者的生命。

项目成果

Differential Expression of MicroRNAs in Papillary Thyroid Carcinoma and Their Role in Racial Disparity.

• DOI: 10.4172/1948-5956.1000340
• 发表时间: 2015-05
• 期刊: Journal of cancer science & therapy
• 作者: Suresh R;Sethi S;Ali S;Giorgadze T;Sarkar FH
• 通讯作者: Sarkar FH

Exosomes in cancer development, metastasis, and drug resistance: a comprehensive review.

• DOI: 10.1007/s10555-013-9441-9
• 发表时间: 2013-12
• 期刊: CANCER AND METASTASIS REVIEWS
• 影响因子: 9.2
• 作者: Azmi, Asfar S.;Bao, Bin;Sarkar, Fazlul H.
• 通讯作者: Sarkar, Fazlul H.

Critical role of prostate apoptosis response-4 in determining the sensitivity of pancreatic cancer cells to small-molecule inhibitor-induced apoptosis.

• DOI: 10.1158/1535-7163.mct-08-0438
• 发表时间: 2008-09
• 期刊: Molecular cancer therapeutics
• 影响因子: 5.7
• 作者: Azmi AS;Wang Z;Burikhanov R;Rangnekar VM;Wang G;Chen J;Wang S;Sarkar FH;Mohammad RM
• 通讯作者: Mohammad RM