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

描述（由申请人提供）： 根据NCI数据库，2011年美国将发生约39，400例口腔鳞状细胞癌（OSCC）新发病例和7，900例死亡。尽管做出了广泛的努力，OSCC的生存率仍然是美国实体瘤中最低的。这一事实强调了通过更有效的OSCC化学预防获得更好结果的必要性。以前的OSCC化学预防试验依赖于全身性药物递送，在很大程度上是不成功的。全身递送的局限性，包括不能在靶部位达到治疗水平和全身毒性，促使我们开发适合于局部药剂递送的制剂。在我们的试点口腔癌化学预防试验中，局部应用生物粘附性冻干黑树莓（BRB）凝胶消退口腔上皮发育不良（OED）病变，没有任何有害的副作用。然而，对于某些OED病变，BRB凝胶还不够。我们随后开发了一种粘膜粘附芬维A胺贴剂，可将治疗水平的合成维生素A类似物芬维A胺递送至口腔粘膜。贴剂递送的芬维A胺避免了先前报道的全身毒性，并将化学上独特的、非常有前途的化学预防剂引入局部递送的OSCC化学预防组合。值得注意的是，细胞因子和炎症丰富的环境，扰乱氧化还原介导的信号传导和巯基依赖性蛋白，驱动OED发展为明显的OSCC。此外，由BRB和芬维A胺调节的许多细胞途径依赖于含有氧化还原敏感性硫醇的蛋白质。因此，我们假设BRB和芬维A胺调节负责基于氧化还原的信号传导和生长调节的硫醇依赖性蛋白质的能力是其化学预防功效的组成部分。因此，本提案的具体目的是：1）研究BRB和芬维A胺对体外口腔角质形成细胞生长和向致瘤表型转变的调节的作用。2)优化BRB和芬维A胺局部给药制剂用于口腔癌化学预防，3)使用两种互补的小鼠模型研究局部给药的BRB和芬维A胺的疗效、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）。基于其独特的作用机制，我们预计优化的BRB和芬维A胺联合给药方案将引起最佳反应，例如增加角质形成细胞终末分化和减少促炎性和血管生成细胞因子的产生。在体内，由于血管生成和角质形成细胞和内皮细胞的移动性减少，治疗效果将表现为进展（原发性）或肿瘤大小（继发性）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.