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: 10158464
• 负责人: Sharon R. Pine
• 金额: $ 43.02万
• 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 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10158464
• 关键词: Address; African American; 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/antagonist; 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.

肺癌是美国和世界范围内所有癌症死亡的主要原因。肺癌风险与生存率 在美国人口中分布不均。非裔美国人男性患乳腺癌的几率更高 与欧美男性相比，肺癌的存活率更低，即使在扣除吸烟和 社会经济因素。导致种族差异的肿瘤特异性生物因素尚不清楚 明白了。该项目的目标是定义JAK/STAT3途径的运行机制 作为非小细胞肺癌(NSCLC)种族健康差异的关键生物学因素，尤其是 肺腺癌(LUAD)是肺癌最常见的组织学亚型。我们的初步数据 提示非裔美国人的LUAD比欧洲裔美国人的LUAD更有可能患有 JAK/STAT3通路突变直接诱导细胞信号转导和激活因子持续激活 转录-3(STAT3)。STAT3是一种癌基因转录因子，在许多癌症中都被过度激活。它 促进调节抗凋亡反应、血管生成、细胞增殖、肿瘤等基因的表达 进展和治疗耐药。此应用的前提是JAK/STAT3信令轴是 由非裔美国人比欧洲人更常见的LUAD突变不适当地激活 这种治疗干预将对部分分子亚群的患者产生临床益处。 路德。鉴于分子亚群在非裔美国人中更为常见，对这一主题的研究可能 帮助缩小健康差距。目标1将描述非洲LUAD的分子特征 美国人和欧洲美国人关注JAK/STAT3及其对种族差异的影响。在目标2中，我们 将利用CRISPR介导的基因组编辑来处理来自LUAD肿瘤的患者来源的癌症模型 非裔美国人和其他模型，以测试STAT3异常激活导致 JAK/STAT3通路中的特定突变，以及这些突变导致LUAD的发生和肿瘤 进步。在目标3中，利用主要来自非裔美国人的患者来源的LUAD异种移植，我们 将检验我们确定的JAK/STAT3途径突变可以作为预测因素的假设 LUAD中STAT3阻断的有效抗肿瘤效应的生物标志物，我们将进一步阐明新的 有效的肿瘤反应的生物标志物。在这个项目结束时，我们将发现一组新颖的 非小细胞肺癌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，他们将 为未来的临床试验提供了一条途径，这些试验可能会改善LUAD患者的临床结果，并有助于减少 肺癌的健康差距。