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.

项目总结 尽管五年的总体存活率令人沮丧，但对治疗的应答率中等，而且 自杀率最高的癌症患者，人类乳头瘤病毒阴性的头颈部鳞状细胞 癌症(HNC)如果及早诊断是可以治愈的。口腔上皮异型增生与口腔扁平苔藓 (OLP)是潜在的癌前病变，为根除疾病提供了一个窗口。现行的标准是 对这些前驱病变的护理包括HE组织学分级和长期临床随访。大部分 OEDs和OLP不会进展为癌症。然而，一个重大的挑战是，不可能维持 为每个患有OED或OLP的患者进行高频随访。新兴的辅助临床技术经常 根据他们检测“高级别”OED的能力来评估诊断的成功率。然而，世卫组织组织学 在确定转化风险方面，OED评分几乎没有(如果有的话)预测价值。此外， OED的组织学分级与Kappa值和Kappa值的观察者间和观察者内的一致性较低 协议的强度被评为轻微到差。因此，美国牙科协会并不建议 任何针对OED/OLP的辅助诊断方式。在我们部署有效的早期检测技术之前， 我们必须提高对高风险OEDs生物学的理解。我们首先从几十年的临床经验中学习 观察。在临床检查中，红斑的颜色变化和硬化需要进行活检。 这些特征表明启动的微环境中的早期炎症和机械变化。 HNC。因此，我们创造了高保真的基因工程小鼠模型来概括这些免疫 以及在HNC启动过程中的机械变化。这些模式是唯一准备建立的 高危标志物因其在口腔粘膜中100%恶变率。通过健壮 在纵向监测中，我们发现了一组最初的免疫代谢标志物，它们的信号出现 在HNC组织学出现之前。该计划将发现一套全面的高风险功能和 采用高级机器学习来生成加权风险分数，该分数将通过我们的 广泛收集低风险白斑和转化的OED/OLP人类标本。为了支持 强大的载玻片技术，我们还开发了一种光学活组织检查工具，获得了美国食品和药物管理局的批准 给药，在低于口腔的显微分辨率下对分子标记进行非侵入性监测 粘膜表面。这一里程碑式的计划将利用高保真的精确度优势 转换OED的建模，广泛的翻译资源，尖端的光学活检平台， 和单细胞技术，在传统的组织学和临床检查中扩展人类的感官 达到了前所未有的分子水平。这一集成工作将为变革性的幻灯片和光盘提供信息 活组织检查辅助工具，可在最早阶段捕获高危OED，以预防HNC。