PROJECT SUMMARY Head & Neck cancer (HNC) is the sixth most prevalent cancer worldwide, with over 600,000 new diagnoses annually. Long-term survival rates for HNC have remained relatively unchanged for the past several decades. Thus, the identification of new targets and therapeutic approaches in HNC are desperately needed. This proposal identifies two new molecular targets in HNC and a new class of inhibitors that show significant promise as new therapies. The molecular targets are signaling complexes organized by syndecans, a family of matrix receptors; they are comprised of integrins, and receptor tyrosine kinases, specifically the epidermal growth factor receptor (EGFR) and insulin-like growth factor-1 receptor (IGF1R). These two kinases are overexpressed in HNC and are known to be causal factors. The integrins that are captured (the ?v?3/?v?5 integrin with IGF1R and the ?6?4 integrin with EGFR) are also known to be causal in HNC, suggesting that the IGF1R- and EGFR-coupled signaling complexes are likely to have central roles in this disease. Competitive peptides (called synstatins or SSTNs) represent a new class of inhibitors that mimic motifs in the extracellular domains of the syndecans and thus block the assembly and signaling of these complexes. Preliminary findings show that the SSTNs block the survival of HNC cells, as well as endothelial cells activated by the tumors to undergo angiogenesis. SSTNs have no effect on normal, resting cells, have no apparent toxicity in animals and are remarkably stable in human plasma and in vivo. We propose to test the hypothesis that these novel synstatins shrink or eradicate HN tumors by targeting the tumor cells as well as the angiogenesis upon which they depend. Specifically, we plan to: (1) Characterize the mechanism of SSTN inhibition of syndecan-coupled EGFR and IGF1R in HNC tumor cells; (2) Evaluate SSTN efficacy in vivo during the progression of HNC from precancerous lesions to tumor formation using the 4-NQO mouse model; and (3) Analyze biomarkers predictive of syndecan-coupled EGFR and IGF1R activity in human tumors and patient-derived HNC xenografts undergoing SSTN therapy. Our goal will be to validate biomarkers that can be used to identify HNC patients that are candidates for SSTN therapy and to demonstrate that SSTNs show significant promise as novel therapeutics for HNC when compared to inhibitors currently in clinical use.