Chemoprevention of Electronic Cigarette Promoted Oral Squamous Cell Carcinoma - Cigarette smoking (CS) is a well-established risk factor for oral squamous cell carcinoma (OSCC), the most common cancer affecting the oral cavity with dismal prognosis even with modern cancer treatment. While cessation efforts are important, many smokers are unable or unwilling to quit, and smokers after short-term cessation will still be at high risk for OSCC. Thus chemo-preventive approaches in those with a history of CS and oral premalignant lesions become attractive. Introduced as a healthy alternative to CS, e-cigarettes (e-cigs) are currently used by approximately 13 million U.S. adults (5%). Our team recently revealed that e-cigs accelerated OSCC xenograft growth and lung metastasis. Importantly, we demonstrated that long-term e-cig exposure, together with 4NQO treatment, induced OSCC in 40% of p53 conditional knockout mice and pre-malignant lesions in an additional 50% of mice. The significance of chromatin histone modulation in e-cigs induced carcinogenesis and cancer-related inflammation, a reversible change with chemo-prevention potential, is being recognized. A recent report revealed e-cigs reduced histone methylation in gingival mesenchymal stem cells; our group found significant accumulation of macrophages and T cells in e-cigs promoted OSCC microenvironment; enhanced expression of lysine demethylase (KDM) 6B and inflammatory genes in e-cigs treated macrophages, reduced by KDM inhibitor. In this proposal, our objective is to establish a screening system and to identify histone modulation enzymes critical for e-cig-promoted oncogenes/pro-inflammatory genes and to establish an animal model testing chemoprevention of e-cigs accelerated OSCC. Our central hypothesis is e-cigs with varied delivery methods and e-liquid compositions differentially accelerate OSCC carcinogenesis, induce oncogene-specific histone modulation in tumor cells and inflammatory gene-specific histone modulation in tumor-associated immune cells, thus providing a model for discovering chemopreventive targets. To translate the histone modulation enzyme inhibitor into clinical chemopreventive therapy, validation in animal models is necessary. Cox-2 inhibitors are classic agents for OSCC chemoprevention with proven effect in animal models. However, the chemopreventive effects of Cox-2 inhibition on e-cig/CS-promoted OSCC in the C57BL/6 K14CreTrp53flo/flo model is unknown. Aim 1. To evaluate the effects of e-cigs on OSCC carcinogenesis and tumor cell/tumor-associated immune cell epigenomic/transcriptomic modulation in C57BL/6K14CreTrp53flo/flo mice. Aim 2. To validate the chemopreventive effects of an anti-inflammatory agent (Cox-2 inhibitor, celecoxib) in e- cig + 4NQO exposure-induced OSCC in C57BL/6 K14CreTrp53flo/flo mice. Future Research Plans: This project will form the basis of an R01 application to study epigenetic-based chemo- preventive approaches targeting e-cig promoted OSCC.
