A Role of Plasminogen in Promoting the Immune Escape in Small Cell Lung Cancer
Abstract
Lung cancer is an urgent priority among Veterans. Small cell lung cancer (SCLC) is the most aggressive form of lung cancer accounting for ~15% of lung malignancies; it is strongly associated with poor survival rates and early metastatic spreading. SCLC is characterized by a low level of cellular differentiation and by multiple different somatic mutations that allow SCLC to easily recur with a radiation and drug-resistant phenotype. The genetic diversity and variability of SCLC made difficult to develop targeting therapies. Therefore, new approaches, which lead to the activation of immune response against SCLC, are urgently needed. The overall long-term goal of this project is to develop a new therapy for SCLC in order to eliminate residual tumor cells, establish immune surveillance, and delay or prevent tumor recurrence. Plasminogen (Pg) is a protein that is abundantly presented in human blood plasma. Pg is the precursor of the fibrinolytic enzyme plasmin (Pn), converted to plasmin by the action of urokinase. Pn is one of the most potent serine proteases that are involved in various physiological processes, including embryogenesis, thrombolysis, wound healing, and cancer progression. The proteolytic activity of Pn is tightly regulated through the activation of its precursor Pg. The concept project will test the idea that the plasminogen activation system (PAS) is involved in immune escape or suppression in SCLC by developing a protective "coat" around the tumor cells, consisting of the plasmin (Pn), plasminogen activation system (PAS), and the fragments of the immunoglobulin G (IgG)s. Eliminating or depleting the cleaved IgGs, from the SCLC patient s blood plasma, will restore the tumor immune surveillance and increase the efficacy of a new adjuvant immunotherapy. Our project is not specifically addressed only to the military group. The results of the project will have a significant impact on the military Service members, Veterans, and their families who are diagnosed with lung cancer and other solid tumors. The results of this concept project will generate new fundamental knowledge about lung cancer and may lead to new areas of research. This work offers to have a very broad impact on research and possibly clinical care of lung cancer. We expect that this new approach will be valid not only for SCLC treatment, but for the other histological types of lung cancers and other solid tumors.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Apr 04, 2016
- Source ID
- W81XWH1510295
Entities
People
- Vera Levina
Organizations
- United States Army
- University of Pittsburgh