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

基本信息

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
项目类别：
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

项目摘要

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.

预计 2018 年美国将新增 51,540 例口咽癌病例，10,030 例死亡。口腔鳞状细胞癌由于其早期疾病的隐匿性，细胞癌（OSCC）是治疗人类最具挑战性的癌症之一，依赖根治性手术进行治疗且难以实现局部控制。此外，甚至 OSCC 患者通过手术治愈的人必须面临面部和口腔的重大美学和功能变化。 OSCC 起源于其前驱病变即口腔上皮内瘤变（OIN）的恶变。虽然并非所有 OIN 都进展到 OSCC，高达 87% 的高危病变发生转化。尽管预测参数得到了完善，但我们还没有方法论预测哪些 OIN 病变将进展为 OSCC。此外，尽管如此，大约三分之一的 OIN 病变仍会复发显微镜下清晰的手术切缘；研究结果暗示角质形成细胞干细胞库存在遗传缺陷。作为 OSCC 的破坏性影响是众所周知的，已经进行了大量的 OSCC 预防试验。大部分这些研究采用全身给药，但基本上无效。全身递送限制包括药物在肝脏首过代谢过程中失活，导致活性药物难以达到治疗水平在目标部位和不良副作用。相比之下，局部递送制剂直接向患者提供治疗水平。治疗部位使用的药物明显较少且无不良副作用。嘴巴的可见可及性方便了代理人患者安置和临床监测。我们实验室此前曾进行过局部递送OSCC化学预防试验并获得了强有力的结果，包括一些患者的 OIN 完全解决。并非所有患者都源自化学预防益处促使开发新的局部给药制剂。本次活动的具体目标建议是：1）确定体内临床先导贴片配方并表征局部递送的代谢特征芬维A胺 (4-HPR)，2) 确认健康参与者的应用时间，然后评估人体的化学预防效果具有显微镜证实的 OIN 病变。实验方法将包括 PK 分析、LC-MS、IHC 和激光捕获显微切割，然后进行 LOH 分析。试验生物标志物（组织学分级、临床表现和 LOH 事件）都与 OIN 进展相关。这种配方，即 4-HPR 贴剂，预计将提供更普遍的效果整个试验队列的化学预防作用。公共卫生相关性：口腔癌，由内壁细胞引起口腔内部的癌症是一种毁灭性的癌症，可以通过积极的手术来治疗。即使通过手术治愈，患者吞咽、进食、说话困难以及面部和口腔畸形。既往口腔癌预防使用可能影响整个身体的药物的计划并不成功，并且经常引起不良副作用包括口腔溃疡和夜盲症。相比之下，该项目引入了一种更高效、更安全的方法，即将癌症预防剂直接应用于癌前组织。