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

University Of Michigan At Ann Arbor, Ann Arbor MI

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Abstract

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.