Project 4 LUNG

项目 4 肺

基本信息

批准号：
10762127
负责人：
Yong Huang
金额：
$ 11.6万
依托单位：
UNIVERSITY OF FLORIDA
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-09-17 至 2026-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10762127
关键词：
3-Dimensional Address Affect African American African American population Alveolar Amides Angiogenesis Inhibition BAY 54-9085 BRAF gene Bioinformatics Biological Biological Factors Biological Models Biomedical Engineering Black American Black Populations Black race Bronchiolo-Alveolar Adenocarcinoma California Carcinogens Caring Cell Line Cell Survival Cells Collection Combined Modality Therapy DNA Data Analyses Development Disparity Doctor of Philosophy Drug Combinations Education Epidermal Growth Factor Receptor Epithelial Cells Erlotinib Ethnic Origin Ethnic Population Florida Formalin Funding Gel Gelatin Gene Mutation Genes Genetic Growth In Vitro Individual Inhalation Invaded KRAS2 gene Knowledge Leukocytes Lung Adenocarcinoma MAP Kinase Gene Malignant Bone Neoplasm Malignant Neoplasms Malignant neoplasm of lung Measures Medicine Metabolism Metastatic Neoplasm to the Bone Methodology Methods Modeling Molecular Mutate Mutation Neoplasm Metastasis Nicotine Organoids PIK3CG gene Paraffin Embedding Pathway interactions Patients Pattern Perfusion Pharmaceutical Preparations Porosity Printing Race Resources Risk Factors STK11 gene Sampling Site Source System TP53 gene Testing Therapeutic Time Tissue Model Tobacco smoke Treatment Efficacy Variant Vascular Endothelial Cell Woman Work alpelisib alveolar epithelium anti-cancer therapeutic anticancer research black men black women bone cancer cell cancer health disparity cytotoxicity driver mutation drug development effective therapy exome sequencing exposure to cigarette smoke follow-up health disparity health equity high risk in vitro Model inhibitor innovation interdisciplinary collaboration member men migration mutant neoplasm registry novel novel therapeutics osteogenic progenitor racial difference racial population response targeted treatment therapeutic evaluation therapeutic target tool treatment response two-dimensional

项目摘要

ABSTRACT – FULL PROJECT 4 LUNG Lung cancer is a prominent source of cancer health disparity, particularly in Black men. While they have lower exposure to cigarette smoke, the most common risk factor for lung cancer, Black men have a 37% higher risk for lung cancer than White men. In addition, the 5-year survival of Black men and women is below that of White subjects. Numerous causes likely underlie these differences, including genetic differences. The latter may affect the metabolism of nicotine/tobacco smoke components, responses to therapy, and differences in cancer driver gene mutations. To understand the effects of the genetic differences between racial/ethnic groups on lung cancer development and treatment, we need to characterize the driver mutations in lung adenocarcinoma (LUAD, the most common type of lung cancer) in Black Americans and develop in vitro lung cancer model systems that reflect the relevant mutations in the correct genetic background. There is a notable lack of cell line models for lung adenocarcinoma from Black Americans, with no Black cell lines from alveolar epithelial cells (the LUAD progenitors) and only 5 known LUAD cell lines (compared to 67 White cell lines). While targeted therapies are available for a subset of LUAD, in vitro systems to test therapeutics in Black Americans are sorely lacking. We hypothesize that due to genetic differences, LUAD in Blacks will have a unique repertoire of cancer driver genes and will respond to targeted therapies distinctly from white LUAD. This proposal represents an interdisciplinary collaboration in which a medicinal (bio)chemist from FAMU (Dr. Lamango), a biomedical engineer from UF (Dr. Huang), and a molecular geneticist from USC (Dr. Offringa) combine their innovative resources to tackle the pronounced health disparities in lung cancer in Black Americans. We will do so through three Specific Aims: In Aim 1, we will identify the main driver mutational signatures of lung adenocarcinoma from 100 Black Americans, who are 5-fold underrepresented in mutational studies. In Aim 2, we will develop new immortalized alveolar and lung adenocarcinoma cell lines from Black subjects and use these and existing cell lines to develop 2- dimensional (2D) and 3-dimensional (3D) in vitro models. We will test promising drugs (polyisoprenylated cysteinyl amide inhibitors (PCAIs)) developed by the Lamango lab, that target the KRAS pathway which is frequently mutated in LUAD. As time allows we will also test other targeted therapeutics and combinations of drugs. In Aim 3 we will develop a novel 3D-printed bone cancer metastasis model to study the differential efficacy of PCAIs and other targeted therapeutics on cancer cell cytotoxicity, migration, and invasion. Bone is the most common metastatic site of LUAD. The three proposed Specific Aims address the lack of knowledge about cancer driver genes in Black American lung adenocarcinoma, generate a collection of normal alveolar and lung adenocarcinoma cell lines from Black subjects that will be used to establish race-appropriate models and will be a great resource for others, and allow the testing of therapeutics on cells from Black Americans using 2D, 3D, and bone metastasis models.

摘要 - 完整项目4肺肺癌是癌症健康差异的重要来源，尤其是在黑人男性中。虽然他们较低暴露于香烟，这是肺癌最常见的危险因素，黑人的风险高37％对于肺癌而不是白人。此外，黑人男女的5年生存率低于白人主题。这些差异可能是许多原因，包括遗传差异。后者可能会影响尼古丁/烟草烟料成分的代谢，对治疗的反应以及癌症驱动因素的差异基因突变。了解种族/族群之间遗传差异对肺癌的影响开发和治疗，我们需要表征肺腺癌中的驱动突变（luad，黑人美国人中最常见的肺癌类型，并开发了体外肺癌模型系统在正确的遗传背景中反映相关突变。缺乏细胞系模型的明显来自黑人美国人的肺腺癌，没有来自肺泡上皮细胞的黑细胞系（luad 祖细胞）和只有5种已知的LUAD细胞系（与67个白细胞系相比）。而目标疗法是可用于LUAD的一部分，非常缺乏在黑人美国人测试治疗的体外系统。我们假设由于遗传差异，黑人中的luad将具有癌症驱动器基因的独特曲目并将对靶向疗法作出明显反应。该建议代表跨学科来自UF的生物医学工程师FAMU（Lamango博士）的医学（BIO）化学家（博士）的合作（博士 Huang），以及来自USC（Offringa博士）的分子遗传学家，结合了他们的创新资源来应对黑人美国人的肺癌的明显健康差异。我们将通过三个特定目标来做到这一点： AIM 1，我们将确定来自100名黑人美国人的肺腺癌的主要驾驶员突变特征，在突变研究中的人数不足的人数不足。在AIM 2中，我们将开发新的永生肺泡和来自黑人受试者的肺腺癌细胞系，并使用这些和现有的细胞系发展2- 尺寸（2D）和3维（3D）体外模型。我们将测试有希望的药物（聚异源肾上腺素）由Lamango Lab开发的Cysteinyl酰胺抑制剂（PCAI），该实验室针对Kras途径经常在luad突变。随着时间的流逝，我们还将测试其他有针对性的治疗和组合毒品。在AIM 3中，我们将开发一种新型的3D打印骨癌转移模型来研究差异效率 PCAI和其他针对癌细胞细胞毒性，迁移和侵袭的靶向疗法。骨头是最大的 LUAD的常见转移部位。提出的三个特定目的解决了缺乏有关癌症的知识黑色美国肺腺癌中的驱动基因，产生正常肺泡和肺的集合黑色受试者的腺癌细胞系将用于建立适合种族的模型，将是对他人来说是一个很好的资源，并允许使用2D，3D对黑人对细胞的治疗进行测试和骨转移模型。