Discovery and therapeutic targeting of biological determinants of lung cancer health disparities

肺癌是美国和全世界所有癌症死亡的主要原因。肺癌风险和生存率 在美国人口中分布不均。非洲裔美国人的发病率更高， 肺癌的存活率比欧美男性更低，即使在调整吸烟和 社会经济因素。导致种族差异的肿瘤特异性生物学因素尚不清楚。 明白本项目的目标是确定JAK/STAT3通路的运作机制 作为非小细胞肺癌（NSCLC）种族健康差异的关键生物学因素， 肺腺癌（LUAD）是肺癌最常见的组织学亚型。我们的初步数据 这表明来自非洲裔美国人的LUAD比来自欧洲裔美国人的LUAD更有可能具有 JAK/STAT3通路突变直接诱导信号转导和激活因子的持续激活， 转录-3（STAT3）。STAT3是一种致癌转录因子，在许多癌症中被过度激活。它 驱动调节抗凋亡反应、血管生成、细胞增殖、肿瘤 进展和治疗抗性。本申请的前提是JAK/STAT3信号传导轴是 在LUAD中，非裔美国人比欧洲人更常见的突变不适当地激活 美国人，治疗干预将是临床受益的一个分子子集的患者， LUAD。考虑到这种分子亚群在非裔美国人中更常见， 帮助缩小健康差距的差距。目的1将描述非洲LUAD的分子特征 美国人和欧洲人关注JAK/STAT 3及其对种族差异的影响。在目标2中， 将利用CRISPR介导的基因组编辑对来自LUAD肿瘤的患者来源的癌症模型进行编辑， 非裔美国人和其他模型，以检验异常STAT3激活是由以下原因引起的假设： JAK/STAT3通路中的特异性突变，并且这些突变驱动LUAD的发展和肿瘤 进展在目标3中，利用主要来自非洲裔美国患者的患者源性LUAD异种移植物，我们 我们将检验我们鉴定的JAK/STAT3通路突变可以作为预测 在LUAD中对STAT3阻断的有效抗肿瘤反应的生物标志物，我们将进一步阐明新的 有效肿瘤反应的生物标志物。在这个项目结束时，我们将发现一套新颖的 NSCLC健康差异的生物学决定因素。如果研究结果支持我们的假设， 为未来的临床试验提供了一条途径，可以改善LUAD患者的临床结局，并有助于减少 肺癌的治疗方法

Lung cancer is the leading cause of all cancer deaths in the U.S. and worldwide. Lung cancer risk and survival are heterogeneously distributed among U.S. populations. African-American men have a higher incidence of and poorer survival from lung cancer than European-American men, even after adjusting for smoking and socioeconomic factors. The tumor-specific biological factors responsible for the racial differences are not yet understood. The goal of this project is to define the mechanisms by which the JAK/STAT3 pathway operates as a key biological contributor of racial health disparities in non-small cell lung cancer (NSCLC), particularly lung adenocarcinoma (LUAD), the most common histological subtype of lung cancer. Our preliminary data suggest that LUADs from African Americans are more likely than LUADs from European Americans to have JAK/STAT3 pathway mutations that directly induce persistent activation of Signal Transducer and Activator of Transcription-3 (STAT3). STAT3 is an oncogenic transcription factor that is hyperactivated in many cancers. It drives expression of genes that regulate anti-apoptotic responses, angiogenesis, cell proliferation, tumor progression, and therapeutic resistance. The premise of this application is that the JAK/STAT3 signaling axis is inappropriately activated by mutations that are more common in LUAD from African Americans than European Americans, and that therapeutic intervention will be of clinical benefit to a molecular subset of patients with LUAD. Given that the molecular subset is more common in African Americans, research on this topic could help narrow the gap in health disparities. Aim 1 will characterize the molecular profiles in LUAD from African Americans and European Americans focusing on JAK/STAT3 and impact on racial differences. In Aim 2, we will utilize CRISPR-mediated genome editing on patient-derived models of cancer from LUAD tumors from African Americans, and other models, to test the hypothesis that aberrant STAT3 activation results from specific mutations in the JAK/STAT3 pathway, and that the mutations drive LUAD development and tumor progression. In Aim 3, utilizing patient-derived LUAD xenografts primarily from African-American patients, we will test the hypothesis that the JAK/STAT3 pathway mutations we identified can serve as predictive biomarkers for effective antitumor response to STAT3 blockade in LUAD, and we will further clarify novel biomarkers of effective tumor response. At the conclusion of this project, we will have uncovered a novel set of biological determinants of NSCLC health disparities. If the results of the study support our hypothesis, they will provide a path to future clinical trials that may improve the clinical outcome of LUAD patients and help reduce lung cancer health disparities.