To develop a novel therapeutic strategy for the treatment of metastatic EGFR over- expressing cancers. EGFR is over-expressed in a variety of solid tumors. The cause of most cancer deaths is cancer metastasis into internal organs that are very difficult to treat. Many of the cancer related deaths are associated with over-expression of EGFR. Thus EGFR is an important candidate for targeted cancer therapy. EGFR targeted antibodies and EGFR targeted kinase inhibitors do not actually cure, whereas the therapy proposed here brings about tumor eradication. Research rationale: An effective cancer therapy should comprise the following features: 1) The drug should affect both the EGFR over-expressing cells as well as neighboring tumor cells with mutated EGFR or no EGFR at all ("bystander effect");2) The agent should activate multiple anti-proliferative/pro-apoptotic pathways to overcome possible mutations and the emergence of drug resistance;3) The drug should eliminate tumor within shortest the possible period and that 4) The therapy should be highly selective for the tumor. Here we describe a novel strategy to selectively induce the death of cancer cells that over-express the EGF receptor, by targeting synthetic death-inducing long chain dsRNA [poly inosine-cytosine (poly IC)] to this receptor, using Poly IC bound to PEI- PEG-EGF in conjunction with PEI-Melittin. Our published data (2006) show that EGFR-targeted poly IC induces rapid apoptosis in the target cells in vitro and in vivo. Expression of several cytokines by transfected target cells and "bystander killing" of neighboring tumor cells were detected in vitro and in vivo. No toxic effects on surrounding normal tissue were observed. Intratumoral delivery of the complex induced the complete regression of pre-established three types of human EGFR over-expressing in nude mice. Very significantly, preliminary results, suggest that the EGFR targeted poly IC can be delivered systemically to eradicate disseminated EGFR over-expressing metastases. Specific Aims: This proposal focuses on 1) the improvement of the efficacy and toxicity of the tested conjugate;2) establishment of luciferase expressing metastatic tumor models which will allow monitoring tumor growth and the efficiency of the therapy in vivo in real time;3) examination of the efficiency and the toxicity of the improved conjugates on the metastatic tumor models;4) Study of the activation of the immune system selectively against poly IC transfected cancer cells. Preclinical development will be initiated immediately after termination of the proposed research, and the optimized conjugate will serve us in the future clinical studies. PUBLIC HEALTH RELEVANCE: The current proposal aims to develop efficient therapy against EGFR over-expressing metastatic tumors. Current treatments of metastatic tumors in many cases require surgery, radiotherapy and chemotherapy, which rarely bring long term remission. The currently used EGFR targeted therapies are rather weakly effective and offer little, if any life prolongation (see above). Our recent mice experiments show that complete cure can be obtained if the targeted Poly IC is injected directly into the EGFR over-expressing tumor. We propose to extend the strategy for local administration of the EGFR targeted Poly IC, to treat EGFR over-expressing orthotropic HNSCC tumor models. We also propose to examine the systemic application of the EGFR targeted Poly IC, to treat EGFR over-expressing metastatic tumor models. Our preliminary results (shown here) support our contention. If successful, this form of therapy could benefit or even cure many cancer patients, without the need for lengthy and expensive procedures.