Full Project 4

完整项目 4

基本信息

批准号：
10762319
负责人：
ITE A OFFRINGA
金额：
$ 12.52万
依托单位：
UNIVERSITY OF SOUTHERN CALIFORNIA
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：
2018-09-20 至 2028-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10762319
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一个重要根源，尤其是黑人男性，尽管他们的患病率较低。接触香烟烟雾是肺癌最常见的危险因素，黑人男性的风险高出 37% 此外，黑人男性和女性的 5 年生存率低于白人。这些差异可能由多种原因造成，包括遗传差异。尼古丁/烟草烟雾成分的代谢、治疗反应以及癌症驱动因素的差异基因突变了解种族/族裔群体之间的遗传差异对肺癌的影响。的发展和治疗，我们需要描述肺腺癌的驱动突变（LUAD，美国黑人中最常见的肺癌类型）并开发体外肺癌模型系统反映正确遗传背景中的相关突变明显缺乏细胞系模型。来自美国黑人的肺腺癌，没有来自肺泡上皮细胞的黑人细胞系（LUAD）祖细胞），并且只有 5 种已知的 LUAD 细胞系（相比之下，有 67 种白细胞系）。我们非常缺乏可用于 LUAD 子集的体外系统来测试美国黑人的治疗方法。研究人员认为，由于遗传差异，黑人的 LUAD 将具有独特的癌症驱动基因库并将对不同于白色 LUAD 的靶向治疗做出反应。该提案代表了跨学科。 FAMU 的医学（生物）化学家（Lamango 博士）和 UF 的生物医学工程师（Lamango 博士）合作。 Huang）和南加州大学的分子遗传学家（Offringa 博士）结合他们的创新资源来解决我们将通过三个具体目标来实现这一目标：目标 1，我们将确定 100 名美国黑人肺腺癌的主要驱动突变特征，在目标 2 中，我们将开发新的永生化肺泡和突变研究中的 5 倍。来自黑人受试者的肺腺癌细胞系，并使用这些细胞系和现有细胞系开发 2- 我们将测试有前途的药物（聚异戊二烯化）。 Lamango 实验室开发的半胱氨酰胺抑制剂 (PCAI)，针对 KRAS 通路如果时间允许，我们还将测试其他靶向治疗方法和组合。在 Aim 3 药物中，我们将开发一种新型 3D 打印骨癌转移模型来研究差异疗效 PCAI 和其他靶向治疗对癌细胞细胞毒性、迁移和侵袭的影响最大。 LUAD 的常见转移部位提出的三个具体目标解决了对癌症知识的缺乏。美国黑人肺腺癌的驱动基因，产生正常肺泡和肺的集合来自黑人受试者的腺癌细胞系将用于建立适合种族的模型，并将对于其他人来说是一个很好的资源，并允许使用 2D、3D、和骨转移模型。