Novel Strategies and Approaches to Improve the Efficacy of Targeted Therapy in Gastric Cancer

Abstract

Gastric cancer (GC) is the third most common cancer and the second most deadly cancer worldwide. The vast majority of GCs are adenocarcinomas, which can be further subdivided into intestinal and diffuse types according to the Lauren classification. In all subtypes, a tumor microenvironment (TME) characterized by active angiogenesis, fibrosis and inflammation is critical in the local and metastatic progression of these tumors. This is in part due to increased hypoxia and suppression of the immune system's ability to fight the cancer. VEGF is a key factor for this abnormal structure and function of the TME of GC. Using surgical samples, we found that tumor angiogenesis is increased with clinical stage progression. In addition, we found that a substantial fraction of GC cells expressed receptor (VEGFR)‐2. Blocking VEGFR2 pathway is a standard of care in GC. However, clinical responses are transient and the survival benefits are limited in GC patients. One of the cues to drive evasive resistance is hypoxia, which can be further increased after treatment with potent anti‐VEGF drugs. Interestingly, using low does anti‐VEGFR‐2 antibodies could transiently normalize tumor vasculature and convert the immunosuppressive TME into an immunostimulatory one. This effect could improve the outcome of various immunotherapies by increasing flow and oxygenation in other cancers. To examine the role of VEGFR‐2 in GC, we blocked VEGFR‐2 in tumor cells versus endothelial cells using species specific monoclonal antibodies and orthotopic models of human GC xenografts in immunodeficient mice. In these experiments, blocking VEGFR2 in endothelial cells normalized tumor blood vessels and reduced hypoxia and fibrosis, which was not seen when blocking VEGFR2 in GC cell. Moreover, a growth delay was seen only when blocking VEGFR2 in endothelial cells. These data are important because anti‐angiogenic therapy might potentially shift the TME towards promotion of anti‐tumor response to other therapies. These studies might lead to rapid implementation of the new combination therapy with anti angiogenic agent into clinical trials through our collaborations.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.