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 cel...