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

局部给药芬维A胺和黑树莓治疗口腔癌的评价

基本信息

批准号：
8523810
负责人：
Susan R Mallery
金额：
$ 29.9万
依托单位：
OHIO STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-09-01 至 2017-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8523810
关键词：
Address Adverse effects Affect Binding Biochemical Biopsy Body part Carcinoma Cessation of life Chemoprevention Chemopreventive Agent Clinical Clinical Research Data Databases Development Disease Dose Drug Formulations Drug Kinetics Economic Burden Electron Transport Environment Enzymes Esthetics Evaluation Event Excision Face Fenretinide Freeze Drying Gel Gene Expression Regulation Growth Human In Vitro Inflammation Inflammation Mediators Intraepithelial Neoplasia Lesion Malignant - descriptor Malignant Neoplasms Mediating Metabolism Modality Modeling Molecular Mus Nature Operative Surgical Procedures Oral Oral cavity Oral mucous membrane structure Outcome Oxidation-Reduction PTGS2 gene Pathology Pathway interactions Patients Pharmaceutical Chemistry Phenotype Premalignant Price Production Property Proteins Radiation Raspberries Recurrence Regional Disease Regulation Reliance Reporting Research Research Methodology Research Personnel Role Schedule Scheme Signal Transduction Site Solid Neoplasm Sulfhydryl Compounds Survival Rate System Techniques Testing Therapeutic Therapeutic Effect Tissues Topical application Toxic effect Vitamin A Xenobiotics analog angiogenesis base cancer chemoprevention cell growth cell growth regulation chemotherapy cytokine disorder control human data in vivo keratinocyte malignant mouth neoplasm metabolic abnormality assessment mouth squamous cell carcinoma oral lesion preclinical study prevent programs psychological trauma public health relevance response socioeconomics transcription factor tumor tumorigenic uptake

项目摘要

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.

描述（由申请人提供）：根据 NCI 数据库，2011 年美国将出现约 39,400 例口腔鳞状细胞癌 (OSCC) 新病例和 7,900 例死亡。尽管付出了大量努力，OSCC 生存率仍然是美国实体瘤中生存率最低的国家之一，这一事实强调了需要通过更有效的 OSCC 化学预防来获得更好的结果。之前的 OSCC 化学预防试验依赖于全身性药物输送，但基本上不成功。全身递送的局限性，包括无法在目标部位达到治疗水平和全身毒性，促使我们开发适合局部药物递送的制剂。在我们的口腔癌化学预防试验中，局部应用生物粘附冻干黑树莓 (BRB) 凝胶可以消退口腔上皮发育不良 (OED) 病变，且没有任何有害副作用。然而，对于一些 OED 损伤，BRB 凝胶是不够的。随后，我们开发了一种粘膜粘附芬维A胺贴剂，可将合成维生素 A 类似物芬维A胺的治疗水平递送至口腔粘膜。贴剂递送的芬维A胺规避了先前报道的全身毒性，并为局部递送的 OSCC 化学预防电池引入了一种化学上独特的、非常有前途的化学预防剂。值得注意的是，富含细胞因子和炎症的环境会扰乱氧化还原介导的信号传导和硫醇依赖性蛋白，从而推动 OED 进展为明显的 OSCC。此外，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对于它们的化学预防功效是不可或缺的。因此，该提案的具体目标是：1) 研究 BRB 和芬维A胺对口腔角质形成细胞生长调节和体外致瘤表型转变的影响。2) 优化 BRB 和芬维A胺局部递送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递送的 BRB 和芬维A胺的功效、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）以及病理学、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：增加角质细胞终末分化并减少促炎和血管生成细胞因子的产生。在体内，治疗效果将表现为由于血管生成以及角质形成细胞和内皮细胞活动性减弱而导致进展（主要）或肿瘤大小（继发）减少。