Chemokine Receptor CCR5: A Novel Target for Inhibiting Small Cell Lung Cancer Growth and Metastasis
Abstract
In the United States, lung cancer is the leading cause of cancer-related mortality. Lung cancer is an urgent priority among Veterans, as evidenced by not only a higher incidence rate, but lower survival in civilian populations. Moreover, military members and beneficiaries are at higher risk of developing lung cancer due to being exposed to environmental carcinogens, stress, and an increased rate of smoking during their Service. Among lung cancer, small cell lung cancer (SCLC) is a highly aggressive sub-type with a limited spectrum of therapeutic options. Most SCLC patients develop drug resistance to known therapies. The area of emphasis of our grant is to identify innovative strategy for treatment of lung cancer. We hypothesize that the chemokine receptor CCR5 plays an important role in suppressing immune response in SCLC. So far, the therapeutic potential of the CCR5 has not been studied for SCLC. In this proposal, we will delineate CCR5-mediated mechanisms in SCLC growth and metastasis. We will further determine the effect of the CCR5 inhibitor Maraviroc on SCLC growth, metastasis, and immune response in different mouse models. We will also determine whether Maraviroc, in combination with other immune activating agent, could be developed as a novel therapeutic strategy to boost immune response against SCLC. Maraviroc is a small molecular weight, moderately lipophilic molecule and is available as film-coated tablets for oral administration. The absorption of Maraviroc is rapid and has not been shown to have any cross-resistance with drugs from other classes. This investigation of the role of CCR5 can open up new therapeutic strategies toward the treatment of highly-fatal SCLC by boosting immune response. Maraviroc has been Food and Drug Administration-approved for other diseases. Because of its minimal adverse effects, lack of generalized toxic effects, and previously demonstrated tolerance in in vivo studies, it possesses a favorable drug safety profile. Thus, this compound may become novel target in clinical trials with relatively quick transition from laboratory to clinic. These studies will not have any short-term effect, but will have long-term effect for military personnel and beneficiaries by developing new treatments to overcome drug resistance for this deadly disease. This is especially imperative, considering the resistance of SCLC to chemotherapy and immunotherapy and the poor prognosis. The proposed research may yield important future clinical therapies, especially immunotherapies for military beneficiaries that are suffering from lung cancer.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010788
Entities
People
- Ramesh K. Ganju
Organizations
- Ohio State University
- United States Army