Assessment of Chemopreventive Effects of a Mucoadhesive Fenretinide Patch on Premalignant Oral Epithelial Lesions

粘膜粘附芬维A胺贴剂对口腔癌前上皮病变的化学预防作用评估

• 批准号: 10321591
• 负责人: Susan R Mallery
• 金额: $ 52.69万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-01-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10321591
• 关键词: 17p13; 9p21; ABL1 gene; Address; Adverse effects; Adverse event; Affect; Affinity; Apoptosis; Basement membrane; Binding; Biological; Biological Markers; Biopsy; Carcinoma; Cells; Cessation of life; Chemicals; Chemoprevention; Chemopreventive Agent; Chemotherapy and/or radiation; Clinical; Clinical Trials; Data; Defect; Deformity; Deglutition; Dependence; Development; Disease; Dose; Drug Kinetics; Eating; Economic Burden; Enteral; Enzymes; Epithelial; Esthetics; Evaluation; Event; Excision; FHIT gene; Face; Fenretinide; Formulation; Fright; Gel; Goals; Growth; Heritability; Heterogeneity; Histology; Histopathologic Grade; Human; In Vitro; Institutional Review Boards; Interferon-alpha; Intraepithelial Neoplasia; Lead; Lesion; Liver; Loss of Heterozygosity; Malignant - descriptor; Malignant Neoplasms; Metabolism; Methodology; Microscopic; Modality; Modeling; Monitor; Mouth Sore; Nature; Night Blindness; Operative Surgical Procedures; Oral; Oral Surgical Procedures; Oral cavity; Oral mucous membrane structure; Oryctolagus cuniculus; Oxides; PTK2 gene; Participant; Patient Agents; Patients; Persons; Pharmaceutical Preparations; Pharmacology; Phase; Phosphotransferases; Polymers; Prevention program; Prevention trial; Protein Tyrosine Kinase; Protocols documentation; Raspberries; Recurrence; Regional Disease; Resolution; SRC gene; STAT3 gene; Saliva; Signal Transduction; Site; Solid; Solid Neoplasm; Solubility; Standardization; Surface; Surgical margins; Survival Rate; System; TP53 gene; Therapeutic; Time; Tissues; Topical application; Toxicology; Tumor Suppressor Genes; UGT1A1 gene; Vitamin A; base; care costs; clinical care; clinically relevant; cohort; compliance behavior; disorder control; exposure route; genomic locus; high risk; in vivo; keratinocyte; large scale production; laser capture microdissection; malignant mouth neoplasm; malignant oropharynx neoplasm; metabolic profile; migration; mouth squamous cell carcinoma; oral cancer prevention; oral cavity epithelium; oral lesion; oral tissue; patient subsets; pill; preclinical study; premalignant; prevent; programs; protein complex; prototype; side effect; socioeconomics; stem cells; systemic toxicity; treatment site; uptake

An estimated 51,540 new oropharyngeal cancer cases and 10,030 deaths will occur in U.S. during 2018. Oral squamous cell carcinoma (OSCC) is one of the most challenging to treat human cancers due to the insidious nature of its early disease, dependence on radical surgery for treatment and difficulty achieving locoregional control. Further, even OSCC patients who are cured by surgery must face major esthetic and functional changes of their face and mouth. OSCC arises from malignant transformation of its precursor lesion i.e. oral intraepithelial neoplasia (OIN). While not all OINs progress to OSCC, up to 87% of high-risk lesions transform. Despite refined predictive parameters, we do not yet have the methodology to predict which OIN lesions will progress to OSCC. Further, approximately a third of OIN lesions recur despite microscopically clear surgical margins; findings which imply heritable defects in the keratinocyte stem cell pool. As OSCC's devastating effects are well-recognized, numerous OSCC prevention trials have been conducted. The majority of these studies employed systemic delivery and were largely ineffective. Systemic delivery limitations include drug inactivation during first pass metabolism in the liver which results in difficulty achieving therapeutic levels of active drug at the target site and adverse side effects. In contrast, local delivery formulations provide therapeutic levels directly to the treatment site using appreciably less drug and without adverse side effects. The mouth's visible accessibility facilitates agent placement by patients and clinical monitoring. Our lab has previously conducted a local delivery OSCC chemoprevention trial and obtained strong results including complete OIN resolution in some patients. Not all patients derived chemopreventive benefits which prompted development of a new local delivery formulation. The Specific Aims of this proposal are: 1) identify the clinical lead patch formulation in vivo and characterize the metabolic profile of locally delivered fenretinide (4-HPR), 2) confirm application time in healthy participants then evaluate chemopreventive efficacy in persons with microscopically confirmed OIN lesions. Experimental methodology will include PK analyses, LC-MS, IHC and laser capture microdissection followed by LOH analyses. The trial biomarkers (histologic grade, clinical presentation and LOH events) are all associated with OIN progression. This formulation i.e. a 4-HPR patch is expected to provide more pervasive chemopreventive effects across the trial cohort. Public Heath Relevance: Oral cancer, which arises from the cells lining the inside of the mouth, is a devastating cancer that is managed by aggressive surgery. Even if cured by surgery, patients live with swallowing, eating, talking difficulties and deformities to their face and mouth. Previous oral cancer prevention programs, which used pills that could affect the entire body, were not successful and often caused adverse side effects including very sore mouths and night blindness. In contrast, this project introduces a more efficient and safer approach i.e. application of the cancer preventing agent directly to the precancerous tissue.

2018年，美国将在美国发生51,540例新的口咽癌病例和10,030例死亡。 细胞癌（OSCC）是由于其早期疾病的阴险性质，是治疗人类癌症的最具挑战性的一种 依赖对治疗的根治性手术和难以获得局部控制的控制。此外，即使是OSCC患者 通过手术治愈的人必须面对脸部和口腔的重大审美和功能变化。 OSCC来自 其前体病变的恶性转化，即口腔内肿瘤（OIN）。虽然并非所有的OIN都会发展为 OSCC，高危高危病变的87％变化。尽管有精致的预测参数，但我们尚无方法论 预测哪些OIN病变将发展为OSCC。此外，尽管 显微镜清晰的手术边缘；意味着可遗传的缺陷在角质形成干细胞池中。作为 OSCC的毁灭性效果已得到充分认可，已经进行了许多OSCC预防试验。大多数 这些研究采用了全身性传递，并且在很大程度上无效。全身递送限制包括药物 肝脏中第一次世纪代谢期间的失活，这导致难以达到活性药物的治疗水平 在目标部位和不良副作用。相比之下，本地交付配方直接提供治疗水平 治疗部位使用明显的药物较少，没有不良副作用。嘴可见的可及性有助于代理 由患者和临床监测放置。我们的实验室以前已经进行了本地交付OSCC化学预防 试验并获得了很强的结果，包括某些患者的完全解决方案。并非所有患者衍生 化学预防效果促使新的本地交付配方开发。这个特定的目的 建议是：1）确定体内的临床铅斑块配方，并表征局部递送的代谢概况 芬雷丁胺（4-HPR），2）确认在健康参与者中的应用时间，然后评估人的化学预防功效 带有显微镜确认的OIN病变。实验方法将包括PK分析，LC-MS，IHC和激光 捕获显微解剖，然后进行LOH分析。试验生物标志物（组织学等级，临床表现和LOH 事件）与OIN进展有关。此公式，即预计4-HPR贴片将提供更多的普遍性 试验队列中的化学预防作用。公共荒地相关性：口腔癌，由细胞衬里引起 口腔内部是一种由侵略性手术管理的毁灭性癌症。即使通过手术治愈，患者也 吞咽，饮食，说话的困难和畸形。以前的口腔癌预防 使用可能影响整个身体的药丸的程序没有成功，并且经常造成不利的副作用 包括嘴巴酸痛和夜间失明。相比之下，该项目引入了一种更高效，更安全的方法，即 直接在癌前组织中施用癌症。