Wednesday, April 2, 2025
4/2/2025
Mechanisms of Papillomavirus Tumor Regression by MEK Signaling Inhibition - Project Summary Human papillomaviruses (HPVs) are highly transmissible causative agents of benign and malignant tumors/ neoplasia in squamous epithelium. Despite prophylactic vaccines that prevent infection by up to nine HPV geno- types 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 at least the next two decades. 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 and reduced quality of life. To date, there are no effective antiviral HPV therapies and no cure for HPV infections. Papillomavirus (PV) disease is primarily driven by PV early proteins, E6 and E7. We reported that the cellular MEK/ERK signaling pathway is a critical regulator of HPV oncogene expression and showed that MEK inhibitors (MEKi’s) profoundly suppress HPV E6 and E7 transcription and neoplastic phenotypes in vitro; a systemically delivered MEKi, trametinib, also leads to tumor regression in a mouse PV type 1 (MmuPV1) infection-induced model of HPV disease. However, the mechanisms of MEKi-induced tumor regression are unknown. Our central hypothesis is that MEK inhibition reduces MmuPV1 E6/E7 transcription leading to diminished keratinocyte (KC) proliferation and restored intrinsic immune signaling to activate innate immunocytes and promote tumor regression. Preliminary data support the rationale and feasibility of our approaches. Herein, we will leverage complementary unbiased tissue-based single-cell and spatial transcriptomics coupled to targeted tissue-based approaches quantified using objective morphometric digital pathology. Functional assays will be used to validate key findings. In Aim 1 we will ascertain how MEK inhibition alters intrinsic KC antiviral responses in MmuPV1-infected mouse tumors and HPV-infected rafts. We hypothesize that MEK inhibition coupled to reduced E6/E7 expression leads to restored intrinsic KC immune signaling leading to tumor recruitment of cytotoxic innate immune. In Aim 2 we will define the role of innate immune cells in MmuPV1 tumor growth and MEKi-induced tumor regression. We hypothesize that recruited innate immune cells will display cytotoxic and/or phagocytic activities. In Aim 3 we will determine the extent to which KC demise contributes to MEKi-induced tumor regression. We hypothesize that reduced E6/E7 expression leads to tumor KC apoptosis, and/or terminal differentiation. We envision both reduced KC expansion and innate cell cytotoxicity contribute to MEKi-mediated tumor regression. Defining the contribution of MEKi- induced antiviral effects to decreased KC proliferation and cytotoxicity in tumor regression is likely to reveal additional targets for PV tumor treatment and potential biomarkers to assess in future clinical HPV studies; we will increase our fundamental understanding of MEK signaling control of E6/E7 expression and innate immune dysregulation in PV infections.
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