Tuesday, May 7, 2024
5/7/2024
Project Summary Human papillomaviruses (HPVs) are highly transmissible causative agents of benign and malignant tumors/neoplasia in mucosal and cutaneous squamous epithelium. Papillomavirus (PV) disease is primarily driven by the viral early proteins, E6 and E7. Despite prophylactic vaccines that can prevent infection by up to nine HPV genotypes that cause genital warts, respiratory papillomas, pre-cancerous lesions, and malignancies, millions of unvaccinated people and those with existing infections will develop HPV-related diseases for the next two decades. Unfortunately, treatments for HPV-associated diseases, precancers, and cancers have not been significantly improved for decades; current therapies lack HPV specificity, have high recurrence rates, and pose risk of long-term morbidities with reduced quality of life. To date, there are no effective antiviral HPV therapies and no cure for HPV infections. We recently reported that the cellular MEK/ERK signaling pathway is a critical regulator of HPV early gene expression and showed that MEK inhibitors (MEKi’s) profoundly suppress HPV early gene transcription and neoplastic phenotypes in vitro; systemically delivered MEKi’s also lead to tumor regression in mouse preclinical models of HPV tumorigenesis. However, oral MEKi’s have toxic side effects in humans. As HPV lesions are localized and accessible at superficial epithelial sites, we propose to develop novel topical MEK inhibitor (MEKi) formulations for the treatment of localized HPV-induced diseases. Preliminary data support the feasibility and innovation of our approaches. In this proof-of-concept study, we will leverage complementary preclinical in vitro and in vivo models of PV disease. We will use mucosal- and cutaneous-like in vitro 3D epithelial tissue models to optimize the topical MEKi formulations for delivery to the basal epithelial cells where PV genome persistence is maintained via early gene expression. In Aim 1, we will study how altered formulations affect the depth of epithelial penetration, the longevity of MEK inhibition, and the suppression of viral early gene expression in these in vitro models, which will inform how to alter formulations for testing in the two in vivo MmuPV1 tumor/neoplasia models (Aim 2). Aim 2 will test topical MEKi formulations with the greatest capacity for MEK inhibition in the basal cells in vitro for their ability to cause regression in preclinical murine models of established MmuPV1 dorsal skin tumors and to reduce preneoplastic disease severity and progression in MmuPV1-mediated cervicovaginal disease. Formulations and application frequencies will then be optimized with a goal of achieving MEKi activities that are equal to or greater than those we find via oral MEKi delivery. Successful completion of this project will position us to determine drug pharmacokinetics and confirm the subsequent reduction achieved for systemic drug exposure; we will then submit an FDA investigational new drug application to carry out clinical studies testing the efficacy of a topical MEKi in the treatment of persistent HPV diseases.
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