Epidemiological data demonstrate a strong correlation between frequent consumption of fresh fruits and vegetables and a decreased risk of oral cancer. In support of these data, preclinical studies have demonstrated the remarkable ability of black raspberries (BRBs) to prevent the development of aerodigestive tract tumors in animals, including oral (hamsters), esophagus (rat), and colon (rats). Furthermore, our ongoing Phase I clinical trials have demonstrated the ability of BRBs to modulate inflammatory biomarkers of molecular efficacy in a manner that supports a chemopreventive strategy for oral cancer. From these human clinical trials, we have established a novel molecular signature of clinically relevant, oral mucosa-derived, BRB-responsive biomarkers. Efforts to elucidate the underlying basis of BRB-mediated oral chemoprevention and predictive efficacy to prevent human oral cancer development will require further employment of a suitable animal model with sufficient molecular reagents. While the hamster cheek pouch model has a history of successfully identifying chemicals and foods with cancer preventing activity (including BRBs), exploratory and comparative molecular studies are hampered by the lack of hamster genome information and subsequent lack of reagents and tools for in depth systems biology investigations. Therefore, another suitable animal model of oral cancer must be employed. The rat tongue/4NQO system of oral carcinogenesis represents such an established and well-studied model for the investigation of black raspberry-mediated oral chemoprevention. The present proposal will explore the ability of BRBs to inhibit oral cancer using the rat tongue model and compare the molecular efficacy of BRBs in the rat tongue to that which has been established in human oral tumors and "high-at-risk" mucosa. We hypothesize that the bioactive components in BRBs will inhibit tumorigenesis and decrease the expression of clinically relevant, pro-inflammatory molecular biomarkers associated with oral carcinogenesis. The following Specific Aims uniquely combines aspects of nutrition, molecular efficacy, and cancer prevention to address the proposed hypothesis. Studies proposed in Specific Aim 1 will establish the ability of dietary BRBs or a single BRB bioactive component (ellagic acid;EA) to inhibit tongue lesion formation during 4NQO-induced oral carcinogenesis in F344 rats. Studies proposed in Specific Aim 2 will determine the comparative molecular efficacy of BRBs and EA on rat tongue carcinogenesis using a clinically-relevant transcriptional profile of genes previous shown to be modulated by BRBs in tumor and "high at-risk" oral mucosal cells of oral cancer patients. Following the successful completion of the above Specific Aims, our novel studies will (i) define the chemopreventive potential of dietary BRBs in a rat tongue model of oral cancer, (ii) validate a signature of BRB molecular efficacy in rat oral mucosa that is directly relevant to human oral cancer and (iii) provide a foundation for future mechanistic investigation of oral cancer chemoprevention.
We believe it is important to understand the involvement of whole foods in prevention of oral cancer development. It is therefore essential that we utilize an animal model to study chemoprevention that mimics the response to whole foods that is observed in high-at-risk human oral mucosa in order to establish a firm scientific foundation for biological control of those genes that are disregulated in oral cancer. These preliminary animal studies have the potential to uncover both suspected and unanticipated mechanisms in oral cancer causation and prevention that may provide a rationale for subsequent studies in human oral cancer prevention.