Osteopontin (OPN) is a secreted phosphoprotein that has been implicated in the development andprogression of several solid tumors. In the previous project, we have identified OPN as a secreted marker fortumor hypoxia and a powerful prognostic marker for head and neck (H&N) cancers. It is therefore a naturalprogression for this project to focus on the role of OPN on tumor progression in H&N cancers. The majorgoal of this project is to systematically investigate the effect of OPN and its individual domains on tumorinvasion and metastasis in H&N cancers and to explore the possibility of targeting OPN using OPN blockingantibodies as a novel anticancer therapy. Specifically, we will generate stable cell lines expressing full-lengthOPN, its individual domains or its mutant constructs under a tetracycline-regulatable promoter in an H&Ncancer cell line that is known to have minimal basal OPN expression. We will determine the impact of OPNand its domains on cell invasion and metastasis under normoxia and hypoxia in vitro and in vivo. We will usemolecular tools to explore the mechanisms by which OPN enhances tumor invasion in H&N cancers. At thesame time, we will evaluate the impact of blocking the expression OPN and its domains using domain-specific antibodies (abs) on tumor invasion, growth and metastasis in nude-mouse xenografts and to explorethe use of OPN blocking abs for novel therapy. Dinitrobenzamide mustards (DNBMs) constitute a new andhighly potent class of hypoxic cytotoxins that will be studied in detail in Project 2. Since we have found thatOPN significantly enhances H&N cancer cell invasion and metastasis under hypoxia, we hypothesize thattargeting both OPN and hypoxia may be better than targeting individual component alone. Therefore, the lastspecific aim of the project will evaluate the efficacy of combining OPN abs with PR-104 + radiation on tumorgrowth and metastasis in comparison to each treatment alone. In summary, the proposed aims areintended to answer the fundamental questions about the mechanisms by which OPN enhances themalignant tumor phenotype in H&N cancers and to identify the optimal approach to target thisprotein for clinical use.
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