Project 1: Lung Cancer

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PROJECT 1: PROJECT SUMMARY Lung cancer remains the leading cause of cancer mortality in the United States (U.S.) with a projected estimate of 228,820 new cases and 135,720 deaths from lung cancer in 2020. Nationally, non-Hispanic African American/Black (AA/Black) men have a disproportionately higher incidence and rate of death from lung cancer compared to their non-Hispanic White (White) male counterparts; however, no such lung cancer disparities exist between AA/Black and white women nationally. Notably the increased rates of lung cancer mortality seen in AA/Blacks relative to their white male counterparts appears to be independent of smoking duration, intensity, quit years, and socioecominc status. Moreover, the underlying molecular mechanisms that contribute to increased lung cancer in AA/Black men remains to be fully elucidated. These disparities are likely driven by a complex and poorly understood interaction between inequities in access care, segregation, upstream determinants of health, chronic exposure to community stress, tobacco exposure, and molecular oncogenic drivers. Epigenetic regulation drives normal cellular growth and development, and the deregulation of epigenetic processes are certainly observed in lung cancer. However, epigenetic-based therapeutic targeting in cancers using DNA hypomethylating agents have largely been unsuccessful in clinical trials. Understanding the epigenetic processes associated with increased cancer development and growth can uncover social and biophysical mechanisms of lung cancer contributing to the current lung cancer disparity in AA/Black men. We have identified protein arginine methylation as a potentially exciting novel lung cancer biomarker and potential drug target, protein arginine methyl transferases 6 (PRMT6). We have determined that 1) PRMT6 expression is increased in AA/Black men; 2) smoking stimulates PRMT6 expression; and 3) PRMT6 overexpression in an in vivo model drives lung tumor development. We hypothesize that the combined effects of community stress and smoking in AA/Black men may be contributing to the AA/Black male “Smoking Paradox” and that PRMT6 may serve as a suitable biomarker capturing these combined exposures (i.e. community stress and smoking) with the potential benefit of enhancing early detection of lung cancer in AA/Black men. TRACER Project 1 aims to measure the interaction between the “community-ome” and the molecular determinants of lung cancer to better define the risks among AA/Black men. Gaining a better understanding of PRMT6 and its role as a molecular biomarker will be an important first step to establishing this innovative approach. Project 1 will lay the foundation for a future full SPORE to enhance the identification and screening accuracy for AA/Black men at risk for lung cancer. As such, it has become clear that the addition of molecular biomarkers, e.g. PRMT6 among others, could potentially improve the effectiveness of LCa screening. The findings from the proposed studies are expected to not only make significant contributions to the basic understanding of lung cancer health disparities in AA/Black men, but also assist in developing novel biomarkers for early detection of lung cancer in AA/Black men.