Project 4 LUNG

摘要-完整项目4肺 肺癌是癌症健康差距的一个重要来源，特别是在黑人男性中。而他们有更低的 吸烟是肺癌的最常见危险因素，黑人男性患肺癌的风险高37% 比白人男性更容易患上肺癌。此外，黑人男性和女性的5年存活率低于白人 研究对象。造成这些差异的原因可能有很多，包括遗传差异。后者可能会影响 尼古丁/烟草烟雾成分的代谢、对治疗的反应以及癌症驱动因素的差异 基因突变。了解人种/民族间遗传差异对肺癌的影响 在发展和治疗方面，我们需要确定肺腺癌(LUAD)的驱动突变 最常见的肺癌类型)，并开发出体外肺癌模型系统 在正确的遗传背景下反映相关突变。值得注意的是，目前还缺乏细胞系模型。 美国黑人肺腺癌，无肺泡上皮细胞的黑色细胞系(LUAD) 只有5个已知的LUAD细胞系(与67个白色细胞系相比)。虽然靶向治疗是 可用于LUAD的子集，用于测试美国黑人疗法的体外系统严重缺乏。我们 假设由于遗传差异，黑人的LUAD将具有独特的癌症驱动基因谱系 并将对靶向治疗产生明显不同于白人LUAD的反应。这项提议代表了一种跨学科的 在合作中，来自FAMU的药物(生物)化学家(Lamango博士)、来自UF(Dr.Lamango)的生物医学工程师(Dr.Lamango) 和南加州大学的一位分子遗传学家(奥夫林加博士)结合他们的创新资源来解决 在美国黑人中，肺癌患者的健康状况存在明显的差异。我们将通过三个具体目标来实现这一目标： 目的1，我们将从100名美国黑人中鉴定肺腺癌的主要驱动因素突变特征， 他们在突变研究中的代表性不足5倍。在目标2中，我们将开发新的永生化牙槽和 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的细胞系来开发2- 二维(2D)和三维(3D)体外模型。我们将测试有前景的药物(聚异丙二烯 由Lamango实验室开发的半胱氨酰胺抑制剂(PCAIs)，其靶向是KRAS途径， 在LUAD中频繁突变。如果时间允许，我们还将测试其他靶向疗法和联合治疗 毒品。在目标3中，我们将开发一种新的3D打印的骨癌转移模型来研究不同的疗效 PCAIs和其他靶向治疗药物对癌细胞的细胞毒性、迁移和侵袭的研究。骨头是最多的 LUAD的常见转移部位。提出的三个具体目标解决了对癌症缺乏了解的问题 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株将被用于建立种族合适的模型，并将被 为其他人提供了一个很好的资源，并允许使用2D，3D， 和骨转移模型。

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.