Slit2 as a Novel Regulator of Lung Cancer Microenvironment
Abstract
Small cell lung cancer (SCLC) comprises of 15%-20% of all lung cancer and is an aggressive subtype with poor prognosis. Not many therapies are available for SCLC, and these patients 5-year overall survival is only 5%. Furthermore, SCLC is characterized by high relapse rates and poor prognosis due to late detection, drug resistance, and a lack of specifically targeted therapeutic regimens. Therefore, it is important to develop novel therapies for improving the poor prognosis of SCLC. SCLC tumor cells are surrounded by stroma that contains various cell types, including inflammatory cells. These cells have been shown to enhance tumor growth and drug resistance. It has been shown that these inflammatory cells enhance tumor growth by inhibiting tumor immunity and allowing proliferation of tumor cells, including drug-resistant cells. We are developing novel therapies against SCLC. In this context, we hypothesize that Slit2, a secretory protein, which is downregulated in SCLC, could be used as a novel therapeutic strategy to inhibit SCLC and overcome drug resistance. We observed that lung cancer patients who have higher expression of Slit2 achieve better overall and progression-free survival. However, not much is known about the mechanisms by which Slit2 inhibits SCLC growth. We also hypothesize that Slit2 may improve anti-tumor immunity by inhibiting the recruitment and activity of inflammatory cells. In this study, we will determine if Slit2 inhibits SCLC growth and sensitize drug-resistant SCLC using preclinical mouse models. We will further determine if Slit2 mediates these effects by inhibiting recruitment and activation of inflammatory cells to the tumor stroma. These studies will provide important and novel insights about the role of Slit2 in enhancing anti-tumor immunity by modulating tumor stroma in SCLC. It might also revolutionize the current understanding and treatment of drug resistance in SCLC, based on role of Slit2 in inhibiting functions of inflammatory cells. This is especially imperative when considering the limited therapeutic options available for SCLC. Since drug resistance is the primary contributor to the failure of available therapies, developing Slit2-based therapies against drug-resistant SCLC will have a huge impact on treating SCLC.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 31, 2017
- Source ID
- W81XWH1610182
Entities
People
- Ramesh K. Ganju
Organizations
- Ohio State University
- United States Army