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.
