No abstract

Black raspberries (BRBs) demonstrate potent inhibition of aerodigestive tract carcinogenesis in animal models. However, translational clinical trials evaluating the ability of BRB phytochemicals to impact molecular biomarkers in the oral mucosa remain limited. The present phase 0 study addresses a fundamental question for oral cancer food-based prevention: Do BRB phytochemicals successfully reach the targeted oral tissues and reduce pro-inflammatory and anti-apoptotic gene expression profiles? Patients with biopsy-confirmed oral squamous cell carcinomas (OSCCs) administered oral troches containing freeze-dried BRB powder from the time of enrollment to the date of curative intent surgery (13.9 ± 1.27 days). Transcriptional biomarkers were evaluated in patient-matched OSCCs and non-involved high at-risk mucosa (HARM) for BRB-associated changes. Significant expression differences between baseline OSCC and HARM tissues were confirmed using a panel of genes commonly deregulated during oral carcinogenesis. Following BRB troche administration, the expression of pro-survival genes (AURKA, BIRC5, EGFR) and pro-inflammatory genes (NFKB1, PTGS2) were significantly reduced. There were no BRB-associated Grade 3–4 toxicities or adverse events and 79.2% (N = 30) of patients successfully completed the study with high levels of compliance (97.2%). The BRB phytochemicals cyanidin-3-rutinoside and cyanidin-3-xylosylrutinoside were detected in all OSCC tissues analyzed, demonstrating that bioactive components were successfully reaching targeted OSCC tissues. We confirmed that hallmark anti-apoptotic and pro-inflammatory molecular biomarkers were over-expressed in OSCCs and that their gene expression was significantly reduced following BRB troche administration. Since these molecular biomarkers are fundamental to oral carcinogenesis and are modifiable, they may represent emerging biomarkers of molecular efficacy for BRB-mediated oral cancer chemoprevention.

No abstract

A66 Background Black raspberries represent a food-based chemopreventive agent rich in polyphenolics compounds, including anthocyanins, that have been shown to reduce inflammation. Numerous studies have demonstrated that inflammation plays a prominent role in tumor growth, progression, and metastasis. Common risk factors for oral squamous cell carcinoma (OSCC), such as tobacco use, also contribute to the inflammatory process. Cell culture and animal studies have shown altered gene expression in tumor and diseased tissues following exposure to lyophilized black raspberries (LBR) or their extracts. Consistently, these chemopreventive studies show the ability of LBR to modulate the expression of genes prominently associated with inflammation, including members of the NFκB family. In OSCC cells exposed to LBR extract in culture, we have shown a down-regulation of inflammatory biomarkers, including NFkB1D, NFkB1 and NFkB2. To transition these in vitro findings into an in vivo setting, we have used the hamster cheek pouch (HCP) model of OSCC to demonstrate a striking suppression of oral tumor lesion incidence and multiplicity (Anticancer Res 22, 2002) following dietary LBR treatment. Ultimately, the role of these essential pre-clinical studies is to translate into a human patient-based clinical investigation. Consequently, the aim of our ongoing Phase 1 Clinical Trial is to evaluate the molecular changes in oral cavity tissues following short-term, locoregional, oral exposure to LBR troches. According to protocols approved by the IRB of The Ohio State University, biopsy-confirmed OSCC patients were administered three LBR troches 4x/day (4.3g cumulative dose) between pre-surgical enrollment and their normally scheduled surgery. Tissue biopsies were obtained from tumor and distant normal tissues at enrollment and during surgical resection, after an exposure range of 2.5-34 days. Using a partial interim cohort of patients, NFκB1 was used as a surrogate endpoint biomarker for inflammation in order to assess LBR-dependent gene expression changes. Methods TaqMan real-time PCR assays were used to examine NFkB1 gene expression in a partial interim cohort of 24 patients. Experimental gene expression levels were normalized to GAPDH, RPS18, B2M, HPRT, and ACTB “housekeeping” gene expression levels. The interim patient cohort was stratified into “young” (≤ 45 years of age) and “older” (> 45 years of age) groups for the purpose of this analysis. Results When patients were grouped into young (n = 7) and older (n = 17) populations, statistically significant differences were seen between LBR-modulated NFκB1 expression in tumor tissue compared to pre-treated, patient matched tumor tissue, with regard to age. Patients in the older population showed a significant decrease in NFκB1 expression in tumor tissue following LBR exposure compared to the younger population (p = 0.003). Conclusions These results suggest that inflammation can play a prominent role in the development of OSCC in older patients, and that LBR treatment may help alleviate the pathological effects of the inflammatory process in this population of patients. The lack of significant NFκB1 LBR-dependent modulation in the young OSCC population may signify that NFκB-independent or other functional pathways play an important role in tumorigenesis. Support: NIH/NIDCR R21DE016361, ACS RSGT-06-126-01-CNE Citation Information: Cancer Prev Res 2008;1(7 Suppl):A66.

No abstract