Transient Vanilloid-like Receptor 2: Novel Therapeutic Target Against Drug-Resistant Lung Cancer
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 the higher incidence rate, but their survival is lower than in civilian populations. Moreover, military members and beneficiaries are at a higher risk of developing lung cancer due to being exposed to environmental carcinogens, stress, and the increased rate of smoking during their Service. Among lung cancer, small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC) are highly aggressive sub-types with a limited spectrum of therapeutic options. Most SCLC and NSCLC patients develop drug resistance to known therapies. We are planning to analyze the role of transient vanilloid-like receptor 2 (TRPV2) in enhancing the effect of chemotherapy drugs. In addition, these studies will provide important information about the TRPV2 agonist, cannabidiol (CBD), in inhibiting drug-resistant lung cancer. Using a publicly available dataset, it was found that high TRPV2 mRNA expression correlates with better overall survival and prognosis in lung cancer patients. In addition, CBD was shown to inhibit the growth of NSCLC cell lines and SCLC cell lines in vitro. CBD has also been shown to enhance Doxorubicin uptake through TRPV2 activation. We also showed that CBD inhibits cancer stem cell (CSC) activity. We hypothesize that TRPV2/CBD may inhibit drug-resistant lung cancer by inhibiting lung CSCs. We will test whether CBD enhances the drug response of known chemotherapy in pre-clinical mouse models of SCLC and NSCLC. CBD 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 the laboratory to the clinic. These studies will not have any short-term effect, but will have a long-term effect for military personnel and beneficiaries by development of new treatments to overcome drug resistance for this deadly disease. This is especially imperative, considering the resistance of lung cancer to chemotherapy and the poor prognosis; the proposed research may yield important future clinical therapies for military beneficiaries that are suffering from lung cancer.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1810304
Entities
People
- Ramesh K. Ganju
Organizations
- Ohio State University
- United States Army