Molecular and Cellular Determinants of Malignant Transformation in Pulmonary Premalignancy
Abstract
Lung cancer is the number one cancer killer among active military personnel and Veterans. By virtue of their service, both active military personnel and Veterans are at higher risk for lung cancer than their civilian counterparts, having been exposed to a variety of Service-related carcinogens in addition to cigarette smoke. Mounting evidence links cancer development to somatic mutations. These mutations could alter cell proliferation and survival pathways or contribute to carcinogenesis by modulation of the genetic context and provide a selective advantage to cancer cells. Immune checkpoints are the inhibitory mechanisms crucial for controlling the physiological immune responses. Recent studies demonstrated that immune checkpoints can be de-regulated in cancer and their blockade may enhance the anti-tumor immunity and improve the efficacy of cancer therapy. Pulmonary cells in the field of lung injury can give rise to distinct premalignant lesions that may bear unique genetic aberrations. A subset of these lesions may escape immune surveillance and progress to invasive cancer; however, the mutational landscape that predicts progression has not been determined. The objectives of the proposed studies are (1) to determine the somatic mutations associated with progression of pulmonary premalignancy to invasive lung adenocarcinoma, (2) to evaluate regulation of cell-mediated immunity in the pulmonary premalignancy--lung cancer spectrum, and (3) to relate the tumor microenvironment to whole exome sequencing-defined mutational landscapes in this setting. The proposed studies are relevant to combating the deleterious effects of lung carcinogens. We anticipate that these results will help identify targets for early diagnostics and the development of targeted therapeutic and chemopreventive strategies for lung cancer at its earliest stages. These studies are critically important because patients at risk for lung cancer may have subclinical disease for years prior to presentation and diagnosis. Moreover, the proteins encoded by some of these mutated genes have recently proven to be neoantigenes or targets for new anticancer drug development.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 31, 2017
- Source ID
- W81XWH1610194
Entities
People
- Kostyantyn Krysan
Organizations
- United States Army
- University of California, Los Angeles