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

项目摘要 尽管五年总生存率令人沮丧，对治疗的反应率中等， 自杀率最高的癌症患者中，人乳头瘤病毒阴性的头颈部鳞状细胞癌 癌（HNC）如果早期诊断是可治愈的。口腔上皮发育不良和口腔扁平苔藓 (OLP)是潜在的癌前病变，为疾病根除提供了窗口。现行标准 这些前驱病变的护理涉及H.& E.组织学分级和长期临床随访。大部分 OED和OLP不会进展为癌症。然而，一个重大挑战是， 对每一位OED或OLP患者进行高频率的随访。新兴的辅助临床技术通常 根据其检测“高级”OED的能力评估诊断成功率。然而，世界卫生组织组织 OED的分级在确定转化风险方面几乎没有预测价值。此外该 OED的组织学分级与kappa值之间和观察者内的一致性较低， 一致性强度评级为轻微至较差。因此，美国牙科协会不建议 OED/OLP的任何辅助诊断方式。在我们部署有效的早期检测技术之前， 我们必须提高我们对高风险OED生物学的理解。我们首先从几十年的临床研究中 意见。在临床检查中，如有肿块的颜色变化和硬结，应作活检。 这些特征表明，在启动微环境中的早期炎症和机械变化， HNC。因此，我们建立了高保真的基因工程小鼠模型，以重现这些免疫功能。 以及HNC引发过程中的机械改变。这些模型是独一无二的， 高风险标志物，因为它们在口腔粘膜中的恶性转化率为100%。通过强有力 通过纵向监测，我们发现了一组最初的免疫代谢标志物， 在HNC组织学出现之前。该计划将发现一套全面的高风险特征， 采用先进的机器学习来生成加权风险评分，并通过我们的 广泛收集低风险白斑病和转化OED/OLP人体标本。支持 强大的载玻片技术，我们还开发了一种光学活检工具，由食品和药物管理局批准 给药，以低于口服的显微镜分辨率对分子标志物进行非侵入性监测 粘膜表面。这一里程碑式的计划将利用高保真度的精度优势， 用于改造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，以扩大人类的感官在传统的组织学和临床检查， 达到前所未有的分子水平。这一综合努力将为变革性的幻灯片和光学 辅助活检工具，可在最早阶段捕获高风险OED，以预防HNC。

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.