Friday, April 26, 2024
4/26/2024
Project summary/Abstract The proposed studies focus on recurrent respiratory papillomatosis (RRP), a persistent human papillomavirus (HPV)-driven disease that has significant morbidity yet no FDA-approved treatment options. As the most common benign neoplasm of the larynx in children, RRP is caused by low risk strains of HPV, most commonly HPV6, and presents as recurring epithelial papillomas along the respiratory tract that threaten the airway. Surgeries are non-curative; children undergo an average of 4-5 procedures to remove masses in the first year alone and can face hundreds in their lifetime. The clinical course of RRP thus poses a severe burden as it is unpredictable and carries a risk of malignant conversion when it progresses to other sites in the aerodigestive tract. Despite the use of an array of attempts at off-label adjuvant therapies, no single agent has been effective at eliminating pediatric RRP, and we cannot predict which patients will respond to any particular drug or treatment regimen. A deeper understanding of the viral and cellular drivers of disease is thus essential to identify better therapies. To this end, single cell RNA sequencing (scRNAseq) was performed on RRP-N(ormal) matched specimens from a treatment naïve patient and analysis performed to select candidate viral (HPV6 E5) and cellular (NOTCH signaling) drivers for mechanistic interrogation. Clinical progress in the RRP field has been hindered by the absence of authentic model systems to define and test predictive biomarkers and key regulators of RRP development. Primary monolayer RRP cells from adults, but not children, are reported in the literature. However, monolayer culture is not conducive to the study of HPV-driven disease as the HPV viral life cycle requires 3D differentiated mucosa. Preliminary work in our laboratory establishes a pipeline of internally controlled, patient-specific models of RRP consisting of RRP-N matched patient tissue cultured into 2D primary cells that have been successfully engineered into 3D organotypic epithelial rafts. Tissue specimens and derivative primary cells from 23 patients have been generated for use in the proposed studies. Validation of preliminary transcriptomic and scRNAseq data in 3D organotypic rafts support the feasibility of using these models for the proposed translational studies to identify disease biomarkers, drivers, and molecular targets of RRP. The project is supported out by a team of scientists with a history of collaboration and complementary expertise in epithelial models, scRNAseq, omics methodologies, statistics and pathology, as well as clinicians who care for one of the largest cohort of children and young adults with RRP in the USA.
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