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.

据估计，2018年美国将新增口咽癌病例51,540例，死亡10,030例。口腔鳞状细胞 细胞癌(OSCC)是治疗人类癌症最具挑战性的疾病之一，因为其早期疾病的隐匿性， 依赖根治性手术治疗，难以实现局部区域控制。此外，即使是口腔鳞癌患者 通过手术治愈的人必须面对面部和口腔的重大美学和功能变化。OSCC产生于 其前驱病变即口腔上皮内瘤变(OIN)的恶变。虽然不是所有的OIN都取得进展 口腔鳞癌，高达87%的高危病变转化。尽管改进了预测参数，但我们还没有方法论 以预测哪些OIN病变将进展为口腔鳞癌。此外，大约三分之一的OIN病变复发，尽管 显微镜下清晰的手术切缘；发现角质形成细胞干细胞池中存在可遗传缺陷。AS 口腔鳞癌的破坏性影响是众所周知的，已经进行了许多口腔鳞癌预防试验。大多数人 这些研究采用的是全身给药，基本上没有效果。系统性给药限制包括药物 肝脏首过代谢过程中的失活，导致难以达到有效药物的治疗水平 在靶点和不良反应。相比之下，本地递送制剂直接为患者提供治疗水平 治疗部位用药略少，且无不良反应。嘴巴的可视可及性便于代理 患者放置和临床监测。我们的实验室此前曾在当地进行过口腔鳞癌的化学预防 试验取得了很好的结果，包括在一些患者中完全解决了OIN。并不是所有的患者都是从 化学预防的好处，促使开发了一种新的本地递送配方。这样做的具体目的是 建议如下：1)确定体内的临床铅贴片配方，并表征局部给药的代谢特征 芬维甲素(4-HPR)，2)确定健康受试者的使用时间，然后评估个人的化学预防效果 经显微镜检查证实为OIN病变。实验方法将包括PK分析、LC-MS、IHC和LASER 捕获显微解剖，然后进行杂合性缺失分析。试验生物标志物(组织学分级、临床表现和杂合性丢失) 事件)都与OIN进展有关。这种配方，即4-HPR补丁，预计将提供更普遍的 试验队列中的化学预防作用。公共卫生相关性：口腔癌，由衬里的细胞引起 口腔内侧是一种毁灭性的癌症，通过积极的手术进行治疗。即使通过手术治愈，患者 生活在吞咽、进食、说话困难和面部和嘴巴畸形的情况下。以往的口腔癌预防 使用可能影响全身的药片的计划并不成功，而且经常引起不良副作用。 包括严重的口腔疼痛和夜盲症。相比之下，该项目引入了更有效和更安全的方法，即 将防癌剂直接应用于癌前组织。