Project 1: Lung Cancer

项目一：肺癌

基本信息

批准号：
10493289
负责人：
SERGE PATRICK NANASINKAM
金额：
$ 13.29万
依托单位：
VIRGINIA COMMONWEALTH UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-20 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10493289
关键词：
African American Age Arginine Biological Markers Biophysical Process Black American Cancer Etiology Center for Translational Science Activities Cessation of life Chronic Clinical Trials Communities Complex Crime DNA Death Rate Development Disadvantaged Drug Targeting Early Diagnosis Effectiveness Enzymes Epigenetic Process Event Exposure to Foundations Frequencies Future Growth and Development function Health Health Services Accessibility Human Incidence Individual Inflammatory Inflammatory Response Lead Lung Lung Neoplasms Malignant Neoplasms Malignant neoplasm of lung Measures Methylation MicroRNAs Modeling Molecular Morbidity - disease rate Neighborhoods Nitrogen Not Hispanic or Latino Oncogenic Pathway interactions Pattern Poverty Process Proteins Research Risk Role Smoking Socioeconomic Status Stress Testing The Cancer Genome Atlas Therapeutic Agents Tobacco smoking behavior Tracer Transferase United States Validation Violence Woman Work adolescent smoking allostatic load base black men cancer biomarkers cancer health disparity cell growth epigenetic regulation health disparity improved in silico in vivo in vivo Model innovation lung cancer screening male men methyl group molecular marker mortality mouse model novel novel marker novel therapeutics overexpression promoter protein expression risk prediction model screening segregation smoking initiation smoking prevalence social socioenvironmental factor systemic inflammatory response therapeutic target tobacco exposure translational impact

项目摘要

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.

项目 1：项目摘要据预计，肺癌仍然是美国癌症死亡的主要原因 2020 年，肺癌新增病例为 228,820 例，死亡人数为 135,720 例。在全国范围内，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较高然而，与非西班牙裔白人男性相比，不存在这种肺癌差异；全国 AA/黑人和白人女性之间的肺癌死亡率显着增加。 AA/黑人相对于白人男性同行似乎与吸烟时间、强度、此外，还有导致戒烟年限和社会经济地位的潜在分子机制。 AA/黑人男性肺癌发病率的增加仍有待充分阐明，这些差异可能是由以下原因造成的。获取护理、隔离、上游等方面的不平等之间存在复杂且鲜为人知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因素表观遗传调控驱动正常的细胞生长和发育，以及表观遗传的放松调控。然而，在肺癌中确实观察到了基于表观遗传学的治疗靶向。使用 DNA 低甲基化剂在临床试验中基本上不成功。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当前 AA/黑人男性肺癌差异。已确定蛋白质精氨酸甲基化作为一种潜在的令人兴奋的新型肺癌生物标志物和潜力药物靶标，蛋白精氨酸甲基转移酶6 (PRMT6) 我们确定1) PRMT6 表达为。 AA/黑人男性中增加；2) 吸烟刺激 PRMT6 表达；3) PRMT6 过度表达我们捕捉到了社区压力和肺肿瘤发展的综合影响。 AA/黑人男性吸烟可能导致 AA/黑人男性“吸烟悖论”，PRMT6 可能作为合适的生物标志物，捕获这些暴露（即社区压力和吸烟）与 TRACER 项目 1 旨在增强 AA/黑人肺癌早期检测的潜在益处。测量“社区组”与肺癌分子决定因素之间的相互作用，以更好地定义 AA/黑人男性的风险更好地了解 PRMT6 及其作为分子的作用。生物标志物将是建立这种创新方法的重要第一步，项目 1 将为该方法奠定基础。未来的完整 SPORE 可以提高对有肺病风险的 AA/黑人男性的识别和筛查准确性因此，很明显，添加分子生物标志物（例如 PRMT6 等）可以预防癌症。拟议研究的结果有望提高 LCa 筛查的有效性。不仅对 AA/黑人肺癌健康差异的基本理解做出了重大贡献男性，还协助开发新的生物标志物，用于 AA/黑人男性肺癌的早期检测。