One Patient to Hundreds: Molecular Portraits of Common and Rare Diseases in the Head and Neck
Abstract
A better understanding of the pathophysiology and molecular heterogeneity underlying response to treatment may lead to improved biomarkers and more robust treatment responses. In my thesis, I will discuss three diseases of the head and neck: human papillomavirus-associated oropharyngeal squamous cell carcinoma, idiopathic subglottic stenosis, and anaplastic thyroid cancer. Using these three diseases, I demonstrate the power of translational molecular profiling to understand these diseases at the genetic, transcriptomic, and/or cellular levels. First, I describe our UWO3 prognostic biomarker that may allow personalized treatment decision making in HPV-associated oropharyngeal cancer. Next, I defined the clinical, transcriptional, and cellular landscape of the human epiglottis and subglottis in healthy and diseased states. By studying the disease idiopathic subglottic stenosis, I catalogued the cellular population within the subglottis associated with disease status and clinical outcomes. I uncovered unappreciated plasticity within the subglottis microenvironment and identified potential therapeutics to reverse disease. Furthermore, I unraveled the genomic and evolutionary landscape of anaplastic thyroid cancer (ATC). Subclonal reconstruction provided unambiguous evidence that ATC diverged early from its related but indolent differentiated thyroid cancers. Finally, using biological insights from an ATC patient undergoing therapy, I present evidence that the type II RAF inhibitor naporafenib can overcome treatment resistance in ATC in vitro and in patient-derived xenograft models. I further uncover the mechanisms of innate and acquired resistance. Together, these molecular portraits have provided tremendous insights on disease drivers, discovered biomarkers, nominated drug targets, and presented new opportunities for clinical translation.