Project 1: Lung Cancer

项目一：肺癌

基本信息

批准号：
10290161
负责人：
SERGE PATRICK NANASINKAM
金额：
$ 14.87万
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/10290161
关键词：
African American Age Arginine Biological Markers Biophysical Process 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

African American Age Arginine Biological Markers Biophysical Process 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

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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：项目摘要肺癌仍然是美国癌症死亡率的主要原因（美国），预计估计值 2020年肺癌的228,820例新病例和135,720例死亡。美国/黑人（AA/黑色）男人的肺癌事件和死亡率较高与他们的非西班牙裔白人（白人）男性相比；但是，不存在这种肺癌分布在全国范围内的AA/黑人和白人妇女之间。值得注意的是，在 AA/黑人相对于其白人男性同行似乎独立于吸烟持续时间，强度，退出岁月和社会代理状况。此外，有助于 AA/黑人男性的肺癌增加仍尚待完全阐明。这些差异可能是由访问护理，隔离，上游的不平等现象之间的复杂且不了解的互动健康的决定因素，长期暴露于社区压力，烟草暴露和分子致癌的因素司机。表观遗传调节驱动正常的细胞生长和发育，以及表观遗传学的失调在肺癌中肯定会观察到过程。但是，癌症中基于表观遗传的治疗靶向在临床试验中，使用DNA低甲基化剂在很大程度上没有成功。了解与癌症发展和增长有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了AA/黑人的当前肺癌差异。我们已经确定蛋白精氨酸甲基化是一种潜在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6（PRMT6）。我们已经确定1）PRMT6表达是 AA/黑人人数增加； 2）吸烟刺激PRMT6表达； 3）in in 体内模型驱动肺部肿瘤的发展。我们假设社区压力和在AA/黑人中吸烟可能会为AA/黑人男性“吸烟悖论”做出贡献，而PRMT6可能用作合适的生物标志物，捕获这些合并的暴露（即社区压力和吸烟）在AA/黑人男性中增强肺癌早期发现的潜在好处。 Tracer Project 1旨在衡量“社区 - 组”与肺癌的分子决定剂之间的相互作用以更好定义AA/黑人的风险。对PRMT6及其作为分子的作用有了更好的了解生物标志物将是建立这种创新方法的重要第一步。项目1将奠定基础对于将来的全孢子，可以增强AA/黑人肺风险的识别和筛查准确性癌症。因此，很明显，添加分子生物标志物，例如PRMT6等，可以有可能提高LCA筛选的有效性。拟议研究的发现将有望不仅为AA/黑色的肺癌健康差异的基本理解做出了重大贡献男性，但也有助于开发新型的生物标志物，以早期发现AA/黑人男性的肺癌。