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

• 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
• 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

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(申请人提供)：利用微阵列、定量2D凝胶电泳和数据挖掘，我们最近发现了一种新的预后生物标志物，Fas相关死亡结构域(FADD)，它在许多人类恶性肿瘤中过度表达，如肺、头颈部、脑和成年男性生殖细胞肿瘤。FADD在肺癌中的表达分析表明，FADD的过度表达与不良的临床预后显著相关。免疫组织化学组织芯片分析显示，磷酸化形式的FADD(p-FADD)的升高与Ki67的表达相关，并与不良的临床结局相关。P-FADD表达增加的肿瘤也表现为核因子-KB活化增强，并与细胞周期蛋白B1和细胞周期蛋白D1显著相关。综上所述，我们实验室和其他实验室发表的结果表明，FADD的磷酸化和NF-KB激活之间存在因果关系，这是侵袭性治疗耐药癌症表型的标志。因此，我们假设，消除肿瘤细胞中p-FADD的水平可能会使肿瘤细胞对化疗药物敏感。为了帮助这一假说的实验，我们求助于分子成像工具，并开发了一种PAN FADD激酶报告程序(FKR)，它可以非侵入性地检测p-FADD水平并实时报告。在本研究中，特异性目标1将确定FKR在检测p-FADD状态中的特异性和敏感性，特异性目标2将利用非侵入性分子成像技术的力量来剖析调控FADD磷酸化的表皮生长因子激活的信号级联。在具体目标3中，我们将探索细胞中p-FADD状态与其对化疗药物的敏感性/耐药性之间的关系。在特定的目的4中，我们将利用小鼠异种移植模型，研究p-FADD水平在肿瘤生长和耐药中的作用。这些研究将建立FADD激酶的非侵入性成像方法，了解最终导致FADD磷酸化的信号级联，以及磷酸化FADD在肿瘤生长和耐药中的核心作用。