Molecular Imaging of Phospho-FADD and its role in resistance to therapy

Phospho-FADD 的分子成像及其在治疗耐药中的作用

基本信息

批准号：
8069987
负责人：
Alnawaz Rehemtulla
金额：
$ 27.99万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-07-06 至 2012-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8069987
关键词：
A549 Adaptor Signaling Protein Adult Amino Acids Antibodies Apoptotic Binding Biological Assay Biological Markers Biological Models Bioluminescence Brain C-terminal Cancer cell line Cell Cycle Cell Cycle Progression Cell Line Cell Therapy Cells Cessation of life Clinical Complex Cyclin D1 Cytosol Data Databases Death Domain Disease EGFR Protein Overexpression Embryonic Development Epidermal Growth Factor Epidermal Growth Factor Receptor Erlotinib Event G2/M Transition Genetically Engineered Mouse Germ Cell Cancers Germ cell tumor Glioblastoma Growth Head and Neck Cancer Head and neck structure Human Image Imaging Device Imaging technology Immunohistochemistry In Vitro Investigation Knockout Mice Lead Lung MEKs Malignant Neoplasms Malignant neoplasm of lung Measures Mediating Messenger RNA Methods Microarray Analysis Modeling Molecular Weight Monitor Mus Nuclear Outcome Pathway interactions Patients Peptides Pharmaceutical Preparations Phenotype Phosphorylation Phosphotransferases Play Prevalence Principal Investigator Publishing Receptor Activation Regimen Regulation Reporter Reporting Research Personnel Resistance Resort Role Sampling Sensitivity and Specificity Serine Signal Pathway Signal Transduction Source Staging Structure T-Cell Proliferation Technology Tetracyclines Therapeutic Therapeutic Agents Time Tissue Microarray Two-Dimensional Gel Electrophoresis Up-Regulation Western Blotting Xenograft Model Xenograft procedure aggressive therapy base cancer cell cancer therapy chemotherapeutic agent cyclin B1 cytotoxic data mining imaging modality in vivo inhibitor/antagonist insight male molecular imaging mouse model mutant neoplastic cell overexpression prognostic programs response small hairpin RNA small molecule therapeutic target therapy resistant tumor tumor growth tumor xenograft upstream kinase

项目摘要

DESCRIPTION (provided by applicant): Using microarray, quantitative 2D gel electrophoresis and data mining we recently identified a new prognostic biomarker, Fas-associated death domain (FADD), which is overexpressed in a number of human malignancies such as lung, head and neck, brain and adult male germ cell tumors. Analysis of FADD expression in lung cancer revealed that overexpression of FADD is significantly associated with poor clinical outcome. Immunohistochemistry-based tissue microarray analysis showed elevation of the phosphorylated form of FADD (p-FADD) correlated with ki67 expression and with poor clinical outcome. Tumors with increased p-FADD expression also showed elevated NF-KB activation and significant co-relation with cyclin B1 and cyclin D1. Taken together, published results from our lab and others suggest a causal relationship between the phosphorylation of FADD and NF-KB activation, a hallmark of an aggressive therapy resistant cancer phenotype. Thereby we hypothesize that ablating p-FADD levels in tumor cells may sensitize cancer cells to chemotherapeutic agents. To aid in experimentation of this hypothesis we have resorted to molecular imaging tools and developed a pan FADD kinase reporter (FKR) which non-invasively senses p-FADD levels and reports the same in real time. In the present study specific aim 1 will determine the specificity and sensitivity of FKR in assaying p-FADD status, specific aim 2, will utilize the power of non-invasive molecular imaging technology to dissect the epidermal growth factor activated signaling cascades that modulates FADD phosphorylation. In specific aim 3 we will explore the relationship between p-FADD status in cells and their sensitivity/resistance to chemotherapeutic agents. In specific aim 4 utilizing mouse xenograft model, we will investigate the role of p-FADD levels in tumor growth and resistance to therapy. These studies will establish non-invasive imaging modality for FADD kinases, understanding of signaling cascade that culminate in FADD phosphorylation and the central role of phosphorylated FADD in tumor growth and resistance to therapy.

描述（由申请人提供）：使用微阵列，定量2D凝胶电泳和数据挖掘，我们最近确定了一种新的预后生物标志物，与FAS相关的死亡结构域（FADD），在许多人类的人类恶性肿瘤中过表达，例如肺，脑和脑，脑和成年男性雄性细胞细胞肿瘤。肺癌中FADD表达的分析表明，FADD的过表达与临床结果不良显着相关。基于免疫组织化学的组织微阵列分析表明，FADD（P-FADD）的磷酸化形式升高与Ki67表达相关，并且临床结果差。 P-FADD表达增加的肿瘤还显示NF-KB激活升高，并且与细胞周期蛋白B1和Cyclin D1的显着共同关联。综上所述，我们实验室和其他实验室的结果表明，FADD的磷酸化与NF-KB激活之间存在因果关系，这是一种抗侵袭性治疗的癌症表型的标志。因此，我们假设在肿瘤细胞中消融P-FADD水平可能使癌细胞对化学治疗剂敏感。为了帮助实验这一假设，我们求助于分子成像工具，并开发了PAN FADD激酶报告基因（FKR），该研究者非侵入性地感知P-FADD水平并实时报告相同的水平。在本研究中，具体目标1将确定FKR在测定P-FADD状态的特异性和敏感性（特定目标2）将利用非侵入性分子成像技术的力量来剖析表皮生长因子激活的信号级联，以调节FADD磷酸化。在特定目标3中，我们将探索细胞中P-FADD状态与它们对化学治疗剂的敏感性/抗性之间的关系。在使用小鼠异种移植模型的特定目标4中，我们将研究P-FADD水平在肿瘤生长和对治疗抗性中的作用。这些研究将建立针对FADD激酶的非侵入性成像方式，了解最终在FADD磷酸化中的信号传导级联反应以及磷酸化FADD在肿瘤生长中的核心作用以及对治疗的耐药性。