Project 1: Lung Cancer

项目1：项目概要 肺癌仍然是美国癌症死亡率的主要原因（美国）根据预测， 2020年肺癌新增病例228，820例，死亡135，720例。非西班牙裔非洲人 美国/黑人（AA/黑人）男性肺癌的发病率和死亡率不成比例地高 与非西班牙裔白色（白色）男性相比， AA/黑人和白色女性之间的关系。值得注意的是， AA/黑人相对于他们的白色男性同行似乎是独立的吸烟时间，强度， 戒烟年限和社会经济地位此外，有助于提高免疫力的潜在分子机制 AA/黑人中肺癌的增加仍有待充分阐明。这些差异可能是由一个 获得保健、隔离、上游和下游服务方面的不平等现象之间复杂而又知之甚少的相互作用 健康的决定因素，长期暴露于社区压力，烟草暴露和分子致癌 司机表观遗传调节驱动正常的细胞生长和发育，而表观遗传调节的失调是细胞生长和发育的关键。 在肺癌中确实观察到了这些过程。然而，基于表观遗传学的癌症治疗靶向 使用DNA低甲基化剂在临床试验中大部分是不成功的。了解 与癌症发展和生长增加相关的表观遗传过程可以揭示社会和 肺癌的生物物理机制导致AA/黑人男性目前的肺癌差异。我们 已经确定蛋白质精氨酸甲基化是一种潜在的令人兴奋的新型肺癌生物标志物， 药物靶蛋白精氨酸甲基转移酶6（PRMT 6）。我们已经确定1）PRMT 6表达是 增加AA/黑人男性; 2）吸烟刺激PRMT 6表达;和3）PRMT 6过表达在一个研究中， 体内模型驱动肺肿瘤发展。我们假设社区压力和 AA/黑人男性的吸烟可能导致AA/黑人男性“吸烟障碍”，PRMT 6可能 作为合适的生物标志物，捕捉这些组合暴露（即社区压力和吸烟）， 增强AA/黑人男性肺癌早期检测的潜在益处。TRACER项目1旨在 测量“社区组”和肺癌分子决定因素之间的相互作用， 定义AA/黑人男性的风险。更好地了解PRMT 6及其作为分子生物学的作用 生物标志物将是建立这种创新方法的重要的第一步。项目1将奠定基础 对于未来的完整SPORE，以提高AA/黑人男性肺部风险的识别和筛查准确性 癌因此，已经清楚的是，分子生物标志物的添加，例如PRMT 6等，可以 潜在地提高LCa筛查的有效性。预计拟议研究的结果将 不仅对AA/黑人肺癌健康差异的基本了解做出了重大贡献 男性，而且还有助于开发新的生物标志物，用于AA/黑人男性肺癌的早期检测。

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.