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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要尽管五年总生存率惨淡，但对治疗的反应率中等，并且其中之一癌症患者自杀率最高，人乳头瘤病毒阴性头颈鳞状细胞如果及早诊断，口腔上皮异型增生 (OED) 和口腔扁平苔藓是可以治愈的。（OLP）是潜在的癌前病变，为根除疾病提供了当前的标准。对这些前兆病变的护理涉及 H.&E 组织学分级和长期临床随访。 OED 和 OLP 不会进展为癌症，但一个重大挑战是不可能维持。经常对每位 OED 或 OLP 患者进行高频随访新兴辅助临床技术。根据其检测“高级别”OED 的能力来评估诊断成功然而，WHO 组织学。 OED 的分级在确定转型风险方面几乎没有预测价值（如果有的话）。 OED 的组织学分级与 kappa 值和观察者间和观察者内部的一致性较低因此，美国牙科协会不推荐这种协议。在我们部署有效的早期检测技术之前，OED/OLP 的任何辅助诊断方式。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经验中学习。在临床检查期间，红斑颜色变化和持续时间需要进行活检。这些特征表明启动微环境中的早期炎症和机械变化。因此，我们生成了高保真基因工程小鼠模型来重现这些免疫。以及 HNC 启动过程中的机械变化，这些模型都准备好建立。由于口腔粘膜恶变率高达 100%，因此成为高危标记物。纵向监测，我们发现了一组初始的免疫代谢标记物，其信号出现在 HNC 组织学出现之前，该程序将发现一组全面的高风险特征和采用先进的机器学习来生成加权风险评分，该评分将通过我们的验证大量收集低风险白斑和转化的 OED/OLP 人类标本以支持凭借强大的载玻片技术，我们还开发了光学活检工具，并获得了食品和药物管理局的批准给药，以低于口腔的微观分辨率对分子标记物进行非侵入性监测这个里程碑驱动的计划将利用高保真度的精确度优势。 O 转化ED 建模、广泛的转化资源、尖端的光学活检平台、和单细胞技术，以扩展人类在传统组织学和临床检查中的感官 OED 达到前所未有的分子水平，这一综合努力将为幻灯片和光学带来变革。活检辅助工具可在最早阶段捕获高风险 OED，以预防 HNC。