The prognosis for oral squamous cell carcinoma remains among the lowest of solid tumors. Consequently, early detection of precancerous oral lesions combined with effective approaches to prevent progression to oral squamous cell carcinoma could improve clinical outcomes. Our lab recently completed a Phase I/II chemoprevention trial which evaluated the chemopreventive efficacy of a 10% freeze dried black raspberry topically applied gel in persons with premalignant oral lesions. While the results were promising, not all participants derived equal chemopreventive benefits from gel application. These clinical findings are the basis for the proposed studies, which entail evaluation of a refined chemopreventive formulation, which will contain an anthocyanin-enriched black raspberry extract (BRE) in conjunction with the synthetic vitamin A derivative, fenretinide. Recently, our collaborators identified that black raspberry anthocyanins are key bioactive berry chemopreventives. Although fenretinide is a recognized inducer of epithelial differentiation and apoptosis, a recent oral cancer prevention trial, that evaluated systemic administration of high dose fenretinide, generated negative results. The levels of fenretinide achieved at the target treatment sites were not determined in this trial, which raises questions regarding the ability of systemic delivery to provide therapeutically relevant local levels. Oral cavity suitable formulations, which include patches that readily cross epithelial barriers and also possess high tissue mucoadhesion in the moist oral environment, can be placed directly on lesional tissues. Notably, unlike systemic administration, local formulations deliver a pharmacologic advantage resulting in therapeutically relevant compound levels without systemic effects, e.g., high dose fenretinide is associated with severe mucositis and hyperlipidemia. The proposed augmented chemopreventive formulation will be delivered by mucoadhesive patches, which will increase target tissue adherence and facilitate compound penetration relative to a gel. Based on our in vitro, in vivo and clinical data we propose that patch-mediated local delivery of BRE supplemented with fenretinide will enhance oral SCC chemoprevention. Prior to conduction of human clinical studies, it is necessary to determine chemopreventive mechanisms, inter-agent effects and pharmacokinetic analyses in appropriate models. Accordingly, we propose the following specific aims:
Specific Aim 1. Evaluate the effects of BRE and fenretinide on selected chemoprevention-relevant parameters (apoptosis, differentiation and enzymes associated with sustained inflammation and angiogenesis) in a continuum of cultured human oral keratinocytes.
Specific Aim 2. Employ a rabbit model to conduct pharmacokinetic analyses of mucoadhesive patch delivered target compounds (BRE and fenretinide) and assess the histologic effects of patch application on oral mucosa. It is anticipated that the results obtained from the proposed studies will help provide the basis for future human oral cancer chemoprevention clinical trials.
As the prognosis for oral squamous cell carcinoma remains among the lowest of solid tumors, early detection of precancerous oral lesions combined with effective approaches to prevent progression to oral squamous cell carcinoma could improve clinical outcomes. Previous studies conducted by our lab demonstrate that topical gel application is an effective means to directly deliver therapeutically relevant levels of cancer preventing compounds. The proposed studies will evaluate an augmented chemopreventive formulation to be delivered by mucoadhesive patches, which will increase local delivery at the target site relative to gel application.
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|Holpuch, Andrew S; Phelps, Maynard P; Desai, Kashappa-Goud H et al. (2012) Evaluation of a mucoadhesive fenretinide patch for local intraoral delivery: a strategy to reintroduce fenretinide for oral cancer chemoprevention. Carcinogenesis 33:1098-105|
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|Holpuch, Andrew S; Desai, Kashappa-Goud H; Schwendeman, Steven P et al. (2011) Optimizing therapeutic efficacy of chemopreventive agents: A critical review of delivery strategies in oral cancer chemoprevention clinical trials. J Carcinog 10:23|