Abstract 1478: Endothelial-specific loss of glutaminase normalizes tumor blood vessels and inhibits tumor growth

Abstract

Abstract Abnormal tumor blood vessels with chaotic angiogenic sprouting result in spontaneous hemorrhages and increased interstitial fluid pressure in the tumor microenvironment. These defects of intra-tumoral vessels lead to poor leukocyte trafficking and drug delivery. Although there is a solid published premise for tumor blood vessel normalization, mechanisms of improved tumor vessel quality are only beginning to be investigated. Because tumor vascular endothelial cells are fast growing, they require nutrients to generate biomass that support their proliferative program. Indeed, inhibition of glucose metabolism has been shown to normalize tumor vasculature and improve drug delivery. In addition to glucose, glutamine is also essential for endothelial cell proliferation and angiogenic sprouting. Thus, we hypothesized that tumor associated endothelium may require glutamine metabolism to support their rapid proliferation and blocking glutaminolysis would normalize tumor vasculature. To test this hypothesis, we crossed glutaminase (GLS) floxed (GLS f/f) animals with CDH5 (VE-Cad)-CreER transgenic mice to induce endothelial-specific deletion of GLS upon tamoxifen administration (GLSECKO). We found that there is a decrease in tumor growth in GLSECKO animals compared to WT recipients. Loss of GLS in endothelium leads to a decrease in CD31+ angiogenic sprouts, and a better coverage of SMA+ pericytes in capillaries. We also observed an increase in tomato-lectin perfused blood vessels and a decrease in tissue hypoxia, as judged by pimonidazole stain. Together, these results suggest that endothelial-specific loss of glutaminase normalizes tumor blood vessels. We are currently investigating the effects of endothelial-specific deletion of GLS on endothelial cell metabolism, tumor metastasis, lymphocytes infiltration, and the response to chemotherapy. Success of this project will uncover the role of endothelial glutaminase in tumor vessels. Further, chemotherapies are currently the main treatment for TNBC patients, so improvements in drug delivery will have significant clinical impact. Finally, TNBCs lacking tumor infiltrating lymphocytes (TILS) are poorly responsive to immune checkpoint inhibitors (ICIs). Investigating ways to normalize tumor blood vessels will lay foundation for developing novel therapeutics to increase TILs in immunologically cold TNBCs to increase their response to ICIs. Citation Format: Verra Ngwa, Deanna Edwards, Jin Chen. Endothelial-specific loss of glutaminase normalizes tumor blood vessels and inhibits tumor growth [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1478.