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Principal Investigator: Michelle A Ozbun
Organization: UNIVERSITY OF NEW MEXICO HEALTH SCIS CTR
Fiscal Year: 2024
Award: $190,625
Funding agency: National Institute of Allergy and Infectious Diseases
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.
Terms: <3-D><3-Dimensional><3D><Affect><American><Anal><Animal Model><Animal Models and Related Studies><Anogenital venereal warts><Anti-viral Therapy><Anus><Apical><Atopic Dermatitis><Atopic Eczema><Atopic Neurodermatitis><Basal Cell><Benign><Biochemical><Biology><Body Tissues><Cancer Burden><Cancers><Cell Communication and Signaling><Cell Signaling><Cervical><Clinical Research><Clinical Study><Clinical Trials><Condyloma Accuminata><Condylomata Acuminata><Cutaneous><Cutaneous Disorder><Data><Data Analyses><Data Analysis><Dermatoses><Development><Disease><Disease Progression><Disorder><Disseminated Neurodermatitis><Dorsal><Drug Exposure><Drug Formulations><Drug Kinetics><Drug Therapy><Drugs><Early Gene Transcriptions><Economic Burden><Epidermoid Cell Cancer><Epithelial Cells><Epithelial Dysplasia><Epithelium><FDA approved><Formulation><Frequencies><Gel><Gene Expression><Gene Transcription><General Population><General Public><Generalized Growth><Genetic Transcription><Genital Organs><Genital Warts><Genitalia><Genome><Genotype><Goals><Growth><HPV><HPV E7><HPV infection><HPV oncogene><Health><Histologic><Histologically><Human><Human Papilloma Virus><Human Papillomavirus><Human papilloma viral oncogene><Human papilloma virus infection><Human papillomavirus infection><Immune><Immunes><Immunocompetent><Immunosuppression><Immunosuppression Effect><Immunosuppressive Effect><In Vitro><Individual><Infection><Infection prevention><Infectious Human Wart Virus><Inflammatory><Intracellular Communication and Signaling><Intraepithelial Neoplasia><Intraepithelial Neoplasms><Investigational New Drug Application><Itching><Length of Life><Lesion><Localized Lesion><Longevity><MEK inhibition><MEKs><Malignant Epidermoid Cell Neoplasm><Malignant Epidermoid Cell Tumor><Malignant Neoplasms><Malignant Squamous Cell Neoplasm><Malignant Squamous Cell Tumor><Malignant Tumor><Mediating><Medication><Messenger RNA><Mice><Mice Mammals><Modeling><Modern Man><Morbidity><Morbidity - disease rate><Mucosa><Mucosal Tissue><Mucous Membrane><Murine><Mus><National Cancer Burden><Neoplasms><Oncogenesis><Oncogenic><Oral><Oropharyngeal><Oropharynx><Oropharynxs><Papilloma Viruses><Papillomaviridae><Papillomavirus><Papillomavirus Infections><Pathogenicity><Penetration><Persons><Pharmaceutical Preparations><Pharmacokinetics><Pharmacotherapy><Phenotype><Population><Position><Positioning Attribute><Pre-Clinical Model><Preclinical Models><Prevalence><Prevent infection><Preventative vaccine><Preventive vaccine><Prophylactic vaccine><Proteins><Pruritic Disorder><Pruritis><Pruritus><Psoriasis><QOL><Quality of life><RNA Expression><Recurrence><Recurrent><Regimen><Regulation><Reporting><Respiratory Papilloma><Respiratory Tract Papilloma><Risk><Severities><Severity of illness><Signal Pathway><Signal Transduction><Signal Transduction Systems><Signaling><Site><Skin><Skin Diseases><Skin Diseases and Manifestations><Skin Neoplasms><Skin Tumor><Specificity><Squamous Cell Cancers><Squamous Epithelium><Surface><T-Cells><T-Lymphocyte><Testing><Therapeutic><Tissue Growth><Tissue Model><Tissues><Topical Drug Administration><Topical application><Toxic effect><Toxicities><Transcription><Tumor Burden><Tumor Load><Tumor Promotion><Validation><Venereal Warts><Viral><Viral Activity><Viral Function><Viral Physiology><Work><administer topically><allergic dermatitis><allergic eczema><apply topically><biological signal transduction><cancer progression><cancer risk><cervicovaginal><clinical applicability><clinical application><condyloma><cutaneous disease><data interpretation><deliver topically><dermal disease><dermal disorder><determine efficacy><developmental><disease severity><dosage><drug treatment><drug/agent><efficacy analysis><efficacy assessment><efficacy determination><efficacy evaluation><efficacy examination><efficacy testing><evaluate efficacy><examine efficacy><human model><human papilloma virus E7><human papilloma virus oncogene><human papillomaviral oncogene><human papillomavirus E7><human papillomavirus oncogene><immune competent><immune suppression><immune suppressive activity><immune suppressive function><immunosuppressed><immunosuppressive activity><immunosuppressive function><immunosuppressive response><improved><in vitro Model><in vivo><in vivo Model><inhibitor><inhibitor drug><inhibitor therapeutic><inhibitor therapy><innovate><innovation><innovative><itch sensation><mRNA><malignancy><model of animal><model of human><mouse model><mucosal site><murine model><neoplasia><neoplasm progression><neoplasm/cancer><neoplastic><neoplastic growth><neoplastic progression><non vaccinated><not vaccinated><novel><ontogeny><oral pharyngeal><papilloma virus Infections><pre-clinical><pre-clinical development><precancer><precancerous><preclinical><preclinical development><premalignant><prevent><preventing><psoriasiform><psoriatic><public health relevance><response><side effect><skin disorder><three dimensional><thymus derived lymphocyte><tissue culture><topical administration><topical delivery><topical drug application><topical treatment><topically administered><topically applied><topically delivered><topically treated><treat topically><tumor><tumor progression><tumorigenesis><unvaccinated><validations><viral infectious disease treatment><virtual><wart virus>