Investigating the Role of Leukotriene Pathway in Progression of Lung Cancer and Related Drug Development
Description: Lung cancer is one of the most common cancers and the leading causes of death worldwide. The therapeutic outcome remained unsatisfying due to drug resistance and high recurrent rate, although much improvement has been made in treatment strategy. Because lung cancer is usually diagnosed at advanced stage, developing preventive strategies to reduce lung cancer incidence is as important as improving treatment strategy. Recently, tumor microenvironment has been gradually recognized as a key contributor for carcinogenesis, cancer progression and drug resistance. Many cells in the tumor microenvironment, such as tumor-associated dendritic cells (TADCs), myeloid-derived suppressor cells (MDSCs) and tumor-associated fibroblasts (TAFs), all contribute to the formation of a cancer-promoting hotbed with chronic inflammation. Our recent studies showed anti-CXCL5 antibody, which blocked cancer-promoting CXCL5 from TADCs, increased the anti-cancer effect of gefitinib, demonstrating the potential of developing treatments targeting cancer-microenvironment crosstalk. Although the role of leukotrienes in cancer progression had been more or less discussed in the literature, most of them focused on LTB4-BLT pathway while the role of cysteinyl leukotrienes (LTC4, LTD4 and LTE4) was only discussed in few studies and most of these studies were not done in lung cancer. In addition, the potential of using montelukast, a cysteinyl leukotriene receptor antagonist (LTRA), as a chemo-preventive agent or an adjuvant for standard cancer treatment has been only studied in few animal studies, while none of them were done in lung cancer. Our recent study analyzing Taiwan National Health Insurance Database showed decreased cancer incidence in asthmatic patients taking LTRAs. We also found montelukast, and LTRA, decreased the viability/proliferation of lung cancer cell lines (in vitro) and impeded the growth of implanted tumor in lung cancer-bearing mice (in vivo). In this project, we will further investigate the underlying mechanisms of LTRA’s effect on cell viability/proliferation and migration of lung cancer cells, as well as investigate the role of leukotrienes, especially cysteinyl leukotrienes, in lung cancer-promoting tumor microenvironment, focusing on the interactions between lung cancer cells and other cells such as TADCs, MDSCs and TAFs. We will also screen potential compounds with higher potency to inhibit the idenfied mechanisms. In addition to test the anti-cancer effect of specific inhibitors to the target identified in this project, we have special interest in combining these specific inhibitors with the standard anti-cancer therapy. By investigating the role of leukotriene pathway in carcinogenesis and progression of lung cancer, we believe our project will enrich our understanding in the crosstalk between lung cancer cells and the tumor microenvironment and provide scientific basis for diagnostic and therapeutic opportunities to improve the prevention and care of lung cancer.
Amount: TWD 3,660,000
Funding type: research
Funder scheme: 學術補助
Investigators: 蔡明儒 (lead), 郭柏麟 (co-lead), 許雅玲, 黃明賢, 周世華, 洪仁宇
Institution: 高雄醫學大學附設中和紀念醫院內科部
Subfield: Pharmacology (medical)
Field: Medicine
Domain: Health Sciences
Funded outputs count: 2
Funder award ID: MOST104-2314-B037-034-MY3
OpenAlex ID: G6889850238