An autocrine pathway involving gastrin releasing peptide receptor (GRPR) and its ligand, gastrin-releasing peptide (GRP) has been implicated in carcinogenesis. Clinical trials are underway in lung cancer patients to investigate the efficacy of therapies that specifically interfere with GRP/GRPR. We have extensive evidence implicating TGF-alpha/EGFR autocrine signaling in squamous cell carcinoma of the head and neck (SCCHN), where EGFR expression is associated with decreased survival. EGFR targeting strategies are actively under investigation in patients with SCCHN. G-protein-coupled receptors (GPCRs), like GRPR, have been shown to activate EGFR via several potential pathways. Furthermore, GRPR blockade has been associated with EGFR downmodulation. GRPR signaling has not been investigated in SCCHN. We previously reported that GRPR is upregulated early in SCCHN carcinogenesis, and that abrogation of GRP/GRPR results in SCCHN growth inhibition in vitro and in vivo. We recently reported that GRP stimulates EGFR phosphorylation and mitogenesis through an EGFR-dependent and MAPK-dependent pathway in SCCHN cells. Further evidence implicates cleavage of EGFR proligands (including TGF-alpha and Amphiregulin) and Src family kinases in this process. Therefore, we propose to test the hypothesis that a GRPR autocrine pathway contributes to SCCHN carcinogenesis, in part, via activation of EGFR mitogenic signaling. In aim 1 we propose to determine the molecular mechanism of EGFR activation by GRP in SCCHN by elucidating the role of EGFR ligand and the contribution of Src family kinases. In aim 2, we will investigate the role of EGFR signaling pathways in mediating the biologic effects induced by GRP by determining: a) the EGFR-dependent and EGFR-independent pathways induced by GRP; and b) the additive or synergistic effects of stimulating/inhibiting both EGFR/GRPR on growth and signaling pathways. Aim 3 will determine the mechanisms and anti-tumor efficacy of combined GRPR/EGFR targeting in SCCHN models in vitro and in vivo by elucidating: a) the consequences of GRP/GRPR blockade and EGFR targeting on SCCHN cells in vitro; b) the therapeutic potential of GRP/GRPR targeting in combination with EGFR blockade in SCCHN xenograft models; and c) the mechanism of combination therapy.