R01 CA129609A2 Over 50% of head and neck squamous cell carcinomas (HNSCC) recur despite multimodal therapy. As local treatment failures drive HNSCC morbidity and mortality, identification of effective treatments to prevent local recurrence has the potential to dramatically improve patient survival. One intervention strategy, which has proven effective in the management of both prostate and brain cancers, is the use of biodegradable polymer implants. While polymer implants provide a pharmacologic advantage, therapeutic benefits are highly dependent upon efficacy and possible synergism of the encapsulated agents. We propose to evaluate three derivatives of natural compounds: N-acetylcysteine (NAC), endostatin and a water-ethanol extract of freeze dried black raspberries, RO-ET. Studies in our laboratories have characterized some of the mechanisms by which NAC, endostatin and RO-ET suppress the HNSCC tumorigenic phenotype. NAC serves as a surrogate propeptide and inhibits activation and function of the basement membrane degrading gelatinase, MMP-9. Our data also show that the established angiostatic agent endostatin binds to HNSCC tropomysin microfilaments and inhibits HNSCC migration and invasion. RO-ET elicited a variety of chemopreventive effects in HNSCC cells that included reduction in VEGF release, inhibition of nitric oxide synthase, initiation of apoptosis and induction of differentiation. We hypothesize that the selected agents will reduce intracellular levels of reactive species, inhibit redox mediated gene expression and suppress pathways critical for HNSCC tumorigenesis.
The research aims of this application are to: 1) determine effective agent dosing levels and evaluate agent combinations for synergistic or possible antagonistic effects (Aim 1.a.), 2) evaluate the effects of the chemopreventive agents on tumor-stromal interactions in HNSCC tumor explants (Aim 1.b.), 3) conduct pharmacokinetic analyses and determine therapeutic abilities to suppress HNSCC xenograft tumorigenesis (Aim 2). Public health relevance: Head and neck cancer is a significant worldwide health problem, and a major reason for treatment failure is cancer recurrence. The goal of these studies is to identify effective cancer-preventing compounds for placement in controlled release delivery vehicles for implantation at the surgery site to prevent local treatment failures and inhibit development of new cancers.
Head and neck cancer is a significant worldwide health problem, and a major reason for treatment failure is cancer recurrence. The goal of these studies is to identify effective cancer-preventing compounds for placement in controlled release delivery vehicles for implantation at the surgery site to prevent local treatment failures and inhibit development of new cancers.
|Mallery, Susan R; Tong, Meng; Michaels, Gregory C et al. (2014) Clinical and biochemical studies support smokeless tobacco's carcinogenic potential in the human oral cavity. Cancer Prev Res (Phila) 7:23-32|
|Tong, Meng; Han, Byungdo B; Holpuch, Andrew S et al. (2013) Inherent phenotypic plasticity facilitates progression of head and neck cancer: endotheliod characteristics enable angiogenesis and invasion. Exp Cell Res 319:1028-42|
|Wu, Xiao; Desai, Kashappa-Goud H; Mallery, Susan R et al. (2012) Mucoadhesive fenretinide patches for site-specific chemoprevention of oral cancer: enhancement of oral mucosal permeation of fenretinide by coincorporation of propylene glycol and menthol. Mol Pharm 9:937-45|
|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|
|Mallery, Susan R; Budendorf, Deric E; Larsen, Matthew P et al. (2011) Effects of human oral mucosal tissue, saliva, and oral microflora on intraoral metabolism and bioactivation of black raspberry anthocyanins. Cancer Prev Res (Phila) 4:1209-21|
|Desai, Kashappa-Goud H; Mallery, Susan R; Holpuch, Andrew S et al. (2011) Development and in vitro-in vivo evaluation of fenretinide-loaded oral mucoadhesive patches for site-specific chemoprevention of oral cancer. Pharm Res 28:2599-609|
|Desai, Kashappa Goud H; Olsen, Karl F; Mallery, Susan R et al. (2010) Formulation and in vitro-in vivo evaluation of black raspberry extract-loaded PLGA/PLA injectable millicylindrical implants for sustained delivery of chemopreventive anthocyanins. Pharm Res 27:628-43|