Project Details
Description
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.
Status | Active |
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Effective start/end date | 9/1/23 → 8/31/24 |
Funding
- National Cancer Institute: $110,556.00
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