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

肺癌健康差异的生物决定因素的发现和治疗靶向

• 批准号: 10385769
• 负责人: Sharon R. Pine
• 金额: $ 5.07万
• 依托单位: RBHS -CANCER INSTITUTE OF NEW JERSEY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-05-15 至 2022-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10385769
• 关键词: Address; African American; African American population; American; Antisense Oligonucleotides; Antitumor Response; Apoptotic; Automobile Driving; Behavior; Biological; Biological Factors; Biological Markers; Cancer Biology; Cancer Etiology; Cancer Model; Cancer Patient; Carboplatin; Cell Proliferation; Cells; Cessation of life; Chemoresistance; Classification; Clinical; Clinical Research; Clinical Trials; Clustered Regularly Interspaced Short Palindromic Repeats; Data; Development; Ethnic group; European; Future; Gene Expression; Genomics; Goals; Histologic; IL6 gene; Incidence; Lung Adenocarcinoma; Lung Neoplasms; Malignant - descriptor; Malignant Neoplasms; Malignant neoplasm of lung; Mediating; Modeling; Molecular; Molecular Profiling; Mus; Mutation; Non-Small-Cell Lung Carcinoma; Oncogenic; Organoids; Outcome; PTPRT gene; Paclitaxel; Pathway interactions; Patients; Pattern; Phosphoric Monoester Hydrolases; Plant Roots; Population; Race; Research; Smoking; Socioeconomic Factors; Stat3 protein; Testing; Therapeutic Intervention; Treatment Efficacy; Tumor Biology; Xenograft procedure; addiction; angiogenesis; base; cancer health disparity; cancer risk; cancer survival; chemotherapy; cohort; data integration; genome editing; health disparity; high throughput screening; improved; in vivo; inhibitor; men; migration; molecular subtypes; mortality; multidisciplinary; mutant; novel; novel marker; patient derived xenograft model; patient subsets; pre-clinical; predictive marker; racial difference; racial health disparity; recruit; response; response biomarker; small molecule inhibitor; social health determinants; therapeutic target; therapeutically effective; therapy resistant; transcription factor; transcriptomics; treatment response; tumor; tumor growth; tumor progression; tumorigenic

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.

肺癌是美国和全球所有癌症死亡的主要原因。肺癌风险和生存 在美国人口中分布异质。非裔美国人的发生率更高 肺癌中的生存比欧美男性差，即使在调整了吸烟和 社会经济因素。负责种族差异的肿瘤特异性生物学因素尚未 理解。该项目的目的是定义JAK/STAT3途径运行的机制 作为非小细胞肺癌（NSCLC）种族健康差异的关键生物学因素，特别是 肺腺癌（LUAD），肺癌最常见的组织学亚型。我们的初步数据 表明，来自非裔美国人的luads比欧洲人的luads更有可能 JAK/STAT3途径突变直接诱导信号传感器的持续激活和激活因子的激活因子 转录3（STAT3）。 STAT3是一种致癌转录因子，在许多癌症中被过度活化。它 驱动调节抗凋亡反应，血管生成，细胞增殖，肿瘤的基因表达 进展和治疗性抗性。该应用程序的前提是JAK/STAT3信号轴为 与欧洲人相比，非裔美国人在LUAD中更常见的突变激活 美国人，这种治疗干预将对患者的分子子群具有 卢德。鉴于分子子集在非裔美国人中更为常见，因此对此主题的研究可能 帮助缩小健康差异的差距。 AIM 1将表征非洲LUAD中的分子曲线 美国人和欧洲人专注于JAK/STAT3并对种族差异的影响。在AIM 2中，我们 将利用CRISPR介导的基因组编辑，从患者来源的癌症模型中 非裔美国人和其他模型，以检验以下假设：异常STAT3激活来自 JAK/STAT3途径中的特定突变，并且突变驱动LUAD发育和肿瘤 进展。在AIM 3中，利用主要来自非裔美国人患者的患者来源的LUAD异种移植物，我们 将检验以下假设：我们确定的JAK/STAT3途径突变可以用作预测 生物标志物有效抗肿瘤对LUAD的STAT3封锁的反应，我们将进一步阐明新颖 有效肿瘤反应的生物标志物。在这个项目的结尾，我们将发现一套新颖的 NSCLC健康差异的生物决定因素。如果研究结果支持我们的假设，他们将 提供了未来临床试验的途径，该试验可能会改善LUAD患者的临床结果并帮助减少 肺癌健康差异。