Evaluation of locally-delivered fenretinide and black raspberries for oral cancer

描述(由申请人提供)： 根据NCI的数据库，2011年美国将发生大约39,400例新的口腔鳞状细胞癌(OSCC)病例和7,900例死亡。尽管进行了广泛的努力，口腔鳞状细胞癌的存活率仍然是美国实体肿瘤中最低的之一-这一事实强调了通过更有效的口腔鳞状细胞癌化学预防来获得更好结果的必要性。以前的口腔鳞状细胞癌化学预防试验依赖于全身给药，但大多不成功。全身给药的局限性，包括无法在目标部位达到治疗水平和全身毒性，促使我们开发适合本地药物给药的配方。在我们的口腔癌化学预防试验中，局部应用生物粘附性冷冻干燥黑覆盆子(BRB)凝胶可以消退口腔上皮异型增生(OED)的病变，没有任何有害的副作用。然而，对于一些OED病变，BRB凝胶是不够的。我们随后开发了一种粘附性非维甲酸贴片，将合成维生素A类似物非维甲酸的治疗水平输送到口腔粘膜。贴片递送的非维甲酸规避了以前报道的全身毒性，并引入了一种化学上独特的、非常有希望的化学预防局部递送的口腔鳞癌化学预防电池。值得注意的是，富含细胞因子和炎症的环境扰乱了氧化还原介导的信号和硫醇依赖蛋白，推动了OED向公开的OSCC的发展。此外，许多受BRB和Fenretinide调控的细胞通路依赖于含有氧化还原敏感硫醇的蛋白质。因此，我们假设BRB和Fenretinide调节硫醇依赖的蛋白质的能力负责基于氧化还原的信号和生长调节，这是它们化学预防效果所不可或缺的。因此，本研究的具体目的是：1)研究BRB和Fenretinide在体外对口腔角质形成细胞生长和向致瘤表型转化的调节作用；2)优化BRB和Fenretinide局部给药的处方，用于口腔癌的化学预防；3)用两种互补的小鼠模型研究BRB和Fenretinide局部给药的疗效、代谢和药代动力学。研究方法包括各种生化和分子分析(目标1)、药物化学技术(目标2)和病理学、药代动力学和代谢研究(目标3)。基于它们独特的作用机制，我们预计优化的BRB和Fenretinide联合给药方案将产生最佳的反应--例如。角质形成细胞终末分化增加，促炎症和血管生成细胞因子产生减少。在体内，由于血管生成和角质形成细胞和内皮细胞流动性的减少，治疗效果将表现为进展(原发)或肿瘤大小(继发)减少。

DESCRIPTION (provided by applicant): Per the NCI database, approximately 39,400 new cases of oral squamous cell carcinoma (OSCC) and 7,900 deaths will occur in the U.S. during 2011. Despite extensive efforts, OSCC survival remains among the lowest for solid tumors in the U.S.-a fact which emphasizes the need for better outcomes via more effective OSCC chemoprevention. Previous OSCC chemoprevention trials, which relied upon systemic agent delivery, were largely unsuccessful. The limitations of systemic delivery, which include inability to achieve therapeutic levels at the target site and systemic toxicity, prompted us to develop formulations amenable for local agent delivery. In our pilot oral cancer chemopreventive trial, a topically applied bioadhesive freeze-dried black raspberry (BRB) gel regressed lesions of oral epithelial dysplasia (OED) without any deleterious side effects. For some OED lesions, however, the BRB gel was insufficient. We have subsequently developed a mucoadhesive fenretinide patch that delivers therapeutic levels of the synthetic vitamin A analogue, fenretinide, to oral mucosa. Patch-delivered fenretinide circumvents previously reported systemic toxicities and introduces a chemically distinct, highly promising chemopreventive to the locally delivered OSCC chemoprevention battery. Notably, a cytokine and inflammation-rich environment, which perturbs redox-mediated signaling and thiol dependent proteins, drives the progression of OED to overt OSCC. Furthermore, many cellular pathways modulated by BRB and fenretinide rely upon proteins that contain redox sensitive thiols. We therefore hypothesize that BRB's and fenretinide's abilities to modulate thiol dependent proteins responsible for redox- based signaling and growth regulation are integral to their chemopreventive efficacy. Accordingly, Specific Aims of this proposal are: 1) Investigate the effect of BRB and fenretinide on the regulation of oral keratinocyte growth and transition to the tumorigenic phenotype in vitro., 2) Optimize BRB and fenretinide local delivery formulations for oral cancer chemoprevention., 3) Study the efficacy, metabolism and pharmacokinetics of locally delivered BRB and fenretinide using two complementary murine models. Research methodology includes a variety of biochemical and molecular analyses (Aim 1), pharmaceutical chemistry techniques (Aim 2) and pathology, pharmacokinetics and metabolism studies (Aim 3). Based on their unique mechanisms of action, we anticipate that optimized combined BRB and fenretinide dosing schemes will elicit the best responses-e.g. increased keratinocyte terminal differentiation and diminished proinflammatory and angiogenic cytokine production. In vivo, therapeutic effects will manifest as decreased progression (primary) or tumor size (secondary) due to diminished angiogenesis and keratinocyte and endothelial mobility.