Activation of the epidermal growth factor receptor (EGFR) pathway is an early event in head and neck carcinogenesis. As a result, there has been increased interest in targeting EGFR for chemoprevention. However, given the redundancy in molecular signaling of tumors, it is unlikely that inhibition of EGFR signaling alone would inhibit malignant progression of OSCC. In this regard, natural compounds or nutritional supplements with favorable safety profiles are particularly attractive for use as potential 'bio-adjuvants' for cancer prevention. To this end, our novel approach involves the use of the nutritional supplement, Vitamin D3 (or its active metabolite calcitriol) as a bio-adjuvant to enhance the chemopreventive efficacy of the EGFR inhibitor, Erlotinib. Two of the main downstream effects of the EGFR pathway involve activation of the MAPK- Erk and the PI3K-Akt pathways that are critically involved in cell survival, proliferation and angiogenesis. Calcitriol induces cleavage o MEK in a caspase-dependent manner and also decreases phosphorylation of Erk and Akt, that is necessary for their activation. It is therefore our hypothesis that targeting these interacting signaling pathways with calcitriol (or vitamin D) in combination with Erlotinib will be more effective in preventing oral cancer. The focus of the present work is to conduct a comprehensive preclinical investigation into the chemopreventive potential of this mechanistically-driven against oral cancer. Using carcinogen and PDX models, the proposed research plan will evaluate the chemopreventive efficacy (Aim 1 and 2) and dissect the molecular mechanisms (Aim 3) involved in the response of oral cancers to this combination regimen. Positive results would pave the way for use of vitamin D3 in combination with Erlotinib for the prevention of oral cancer.