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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：
10542711
负责人：
Susan R Mallery
金额：
$ 47.54万
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/10542711
关键词：
17p13 9p21 ABL1 gene Address Adverse effects Adverse event Affect Affinity Aftercare Apoptosis Basement membrane Binding Biological Biological Markers Biopsy Cell Line Cessation of life Chemicals Chemoprevention Chemopreventive Agent Chemotherapy and/or radiation Clinical Clinical Trials Cytoskeleton Data Defect Deformity Deglutition Dependence Development Disease Dose Drug Kinetics Eating Economic Burden Enteral Enzymes Epithelium 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 Invaded Lead Lesion Liver Loss of Heterozygosity Malignant - descriptor Malignant Neoplasms Metabolism Methodology Microscopic Modality Modeling Mole the mammal Monitor Mouth Sore Nature Night Blindness Operative Surgical Procedures Oral Oral Surgical Procedures Oral cavity Oral mucous membrane structure Oryctolagus cuniculus PTK2 gene Participant Patient Agents Patients Persons Pharmaceutical Preparations Phase Phosphotransferases Polymers Prevention program Prevention strategy Prevention trial Proliferating Protein Tyrosine Kinase Protocols documentation Raspberries Recurrence Resolution SRC gene STAT3 gene Saliva Signal Transduction Site Solid Solid Neoplasm Solubility Squamous cell carcinoma Standardization Surface Surgical margins Survival Rate System TP53 gene Therapeutic Time Tissues Topical application Toxicology Tumor Suppressor Genes UGT1A1 gene Vitamin A 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 meter migration mouth squamous cell carcinoma oral cancer prevention oral cavity epithelium oral lesion oral tissue patient subsets pharmacologic pill preclinical study premalignant prevent programs protein complex prototype public health relevance 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.

据估计，2018年美国将发生51,540例新的口咽癌病例和10,030例死亡。口腔鳞状上皮