Full Project 4 - Lung

Lung cancer is a prominent source of cancer death in the US. Numerous factors, including genetic alterations that influence the metabolism of nicotine/tobacco smoke components, responses to therapy, and differences in cancer driver gene mutations, contribute to lung cancer morbidity and mortality. To understand the effects of the genetic factors on lung cancer development and treatment, we need to characterize the driver mutations in lung adenocarcinoma (LUAD), the most common type of lung cancer) and develop in vitro lung cancer model systems that reflect the relevant mutations among individuals at greatest risk for morbidity and mortality from this disease. There is a notable lack of cell line models for lung adenocarcinoma from these individuals and cell lines from alveolar epithelial cells (the LUAD progenitors) do not exist. Only 5 known LUAD cell lines are available for the less studied group compared to 67 cell lines in the more studied group. While targeted therapies are available for a subset of LUAD, in vitro systems to test therapeutics in the groups at greatest risk for morbidity and mortality are sorely lacking. We hypothesize that LUAD will have a unique repertoire of cancer driver genes and will respond to targeted therapies distinctly from LUAD. This Full Projectl 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 these pronounced differences in lung cancer. We will do so through three Specific Aims: In Aim 1, we will identify the main driver mutational signatures of lung adenocarcinoma from 100 individuals at increased risk for lung cancer morbidity and mortality. In Aim 2, we will develop new immortalized alveolar and lung adenocarcinoma cell lines from these patients 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 on the development and treatment of lung adenocarcinoma, generate a collection of normal alveolar and lung adenocarcinoma cell lines that will be used to establish appropriate models that will be a great resource for others, and allow the testing of therapeutics on cells using 2D, 3D, and bone metastasis models.