Advancing On-Slide and Optical Biopsy Tools to Detect High-Risk Oral Premalignancy

先进的载玻片和光学活检工具来检测高风险口腔癌前病变

• 批准号: 10768888
• 负责人: Steven Bennett Chinn
• 金额: $ 68.93万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-21 至 2028-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10768888
• 关键词: Affinity; Agreement; American Dental Association; Ancillary Study; Automobile Driving; Benign; Binding; Biology; Biopsy; CD8-Positive T-Lymphocytes; Cancer Patient; Cells; Clinical; Collection; Color; Complement; Cytology; Detection; Development; Diagnostic; Discriminant Analysis; Disease; Early Diagnosis; Engineering; Epidermal Growth Factor Receptor; Epithelial Cells; Epithelium; Evaluation; Event; Exclusion; Exhibits; FDA approved; Frequencies; Genetically Engineered Mouse; Glycolysis Pathway; Goals; HPV-negative head and neck cancer; Head and Neck Squamous Cell Carcinoma; Histologic; Histology; Histopathologic Grade; Human; Image; Immune; Induration; Inflammatory; Interferon Type I; Intraepithelial Neoplasia; Keratosis; Lasers; Learning; Lesion; Leukoplakia; Lichen Planus; Link; Longitudinal cohort; Machine Learning; Malignant - descriptor; Malignant Neoplasms; Marker Discovery; Mechanics; Membrane; Metabolic; Methods; Microscopic; Modality; Modeling; Molecular; Molecular Target; Monitor; Myeloid Cells; Myeloid-derived suppressor cells; Oncogenes; Oncogenic; Optical Biopsy; Oral Leukoplakia; Oral Lichen Planus; Oral cavity; Oral mucous membrane structure; Pathology; Pathway interactions; Patient Care; Patients; Persons; Phase; Pre-Clinical Model; Prevention; Resolution; Resources; Risk; Risk Marker; SLC2A1 gene; Signal Transduction; Slide; Specimen; Surface; Survival Rate; T-Lymphocyte; Tactile; Technology; Tissues; Tumor Escape; United States Food and Drug Administration; Up-Regulation; Validation; base; cancer risk; clinical examination; clinical translation; clinically significant; cohort; diagnostic criteria; glucose metabolism; high risk; improved; in vivo; malignant mouth neoplasm; mechanical signal; microendoscopy; molecular marker; non-invasive monitor; novel; oral cavity epithelium; oral premalignancy; overexpression; premalignant; prognostic; prognostic value; programs; public health relevance; response; single cell technology; spatial relationship; standard of care; success; suicide rate; tool; tumor DNA

PROJECT SUMMARY Despite the dismal five-year overall survival rate, a moderate response rate to treatments, and one of the highest suicide rates among cancer patients, human papillomavirus-negative head and neck squamous cell carcinomas (HNCs) are curable if diagnosed early. Oral epithelial dysplasias (OEDs) and oral lichen planus (OLP) are potentially premalignant lesions that offer a window for disease eradication. The current standard of care for these precursor lesions involves H.&E. histologic grading and long-term clinical follow-ups. Most of OEDs and OLP do not progress to cancer. However, a significant challenge is that it is impossible to maintain high-frequency follow-ups for every patient with OED or OLP. Emerging adjunct clinical technologies often evaluate diagnostic success based on their power to detect “high-grade” OEDs. However, the WHO histologic grading of OED has little, if any, prognostic value in determining the transformation risks. In addition, the histologic grading of OEDs has low inter-observer and intra-observer consistency with the kappa-values and strength of agreement rated slight-to-poor. As a result, the American Dental Association has not recommended any adjunct diagnostic modalities for OED/OLP. Before we can deploy impactful early detection technologies, we must improve our understanding of the biology of high-risk OEDs. We first learn from decades of clinical observations. During the clinical examinations, erythematous color change and induration warrant a biopsy. These features indicate early inflammatory and mechanical changes in the microenvironment of initiating HNCs. Thus, we generated high-fidelity, genetically engineered mouse models to recapitulate these immune and mechanical alterations over the course of HNC initiation. These models are uniquely poised to establish the high-risk markers due to their 100% malignant transformation rate in the oral mucosa. Through robust longitudinal monitoring, we have uncovered an initial set of immunometabolic markers whose signals emerge before the HNC histology appears. This program will discover a comprehensive set of high-risk features and employ advanced machine learning to generate a weighted risk score, which will be validated through our extensive collections of low-risk leukoplakia and transformed OED/OLP human specimens. To support the robust on-slide technology, we also developed an optical biopsy tool, approved by the Food and Drug Administration, to perform non-invasive monitoring of molecular markers at a microscopic resolution below oral mucosal surfaces. This milestone-driven program will leverage the strengths of precision in high-fidelity modeling for transforming OEDs, the extensive translational resources, a cutting-edge optical biopsy platform, and single-cell technologies to extend the human senses in conventional histology and clinical examination of OED to unprecedented molecular levels. This integrated effort will inform transformative on-slide and optical biopsy ancillary tools to capture high-risk OEDs at the earliest phase for HNC prevention.

项目摘要 尽管五年的总生存率惨淡，对治疗的现代回应率和一个 癌症患者的自杀率最高，人乳头瘤病毒阴性头和颈部鳞状细胞 癌（HNC）如果早点诊断为可治愈。口腔上皮异常增生（OED）和口服地衣平面 （OLP）是潜在的前病变，可提供消除疾病的窗口。当前标准 护理这些前体病变涉及H.＆e。组织学分级和长期临床随访。大多数 OED和OLP不会发展为癌症。但是，一个重大的挑战是无法维持 每个患有OED或OLP患者的高频随访。新兴的辅助临床技术 根据他们检测“高级” OED的能力来评估诊断成功。但是，谁的组织学 OED的评分在确定转化风险时几乎没有预后价值。另外， OED的组织学分级与Kappa值的观察者间和观察者内部的一致性低。 一致性的强度略有冠军。结果，美国牙科协会不建议 OED/OLP的任何辅助诊断方式。在我们可以部署有影响力的早期检测技术之前， 我们必须提高对高风险OED生物学的理解。我们首先从数十年的临床中学习 观察。在临床检查期间，红斑的色彩变化和诱导需要活检。 这些特征表明启动微环境的早期炎症和机械变化 HNCS。这，我们产生了高保真，一般设计的鼠标模型来概括这些免疫 以及HNC启动过程中的机械改变。这些模型是独特的中毒以建立的 高风险标记是由于口服粘膜中的100％恶性转化率而引起的。通过健壮 纵向监测，我们发现了一组初始的免疫代谢标记，其信号出现了 在出现HNC组织学之前。该程序将发现一套全面的高风险功能， 员工高级机器学习以产生加权风险评分，这将通过我们的 大量的低风险白细胞和转化的OED/OLP人类标本。支持 强大的扫描技术，我们还开发了一种光活检工具，由食物和药物批准 给药，以低于口服的微观分辨率对分子标记进行非侵入性监测 粘膜表面。这个里程碑驱动的计划将利用高保真性的精度优势 用于转换OED的建模，广泛的翻译资源，一个尖端的光学活检平台， 和单细胞技术，以扩展人类在常规组织学和临床检查中的感官 OED到前所未有的分子水平。这项集成的工作将为统一和光学的变革性提供信息 在HNC预防的最早阶段捕获高风险OED的活检辅助工具。