Abstract LB-022: Targeting glutamine metabolism as a mean of treating a murine model of ovarian cancer and ascites development
Authors: Oh Min-Hee , Travers Meghan , Brown Stephen , Zhao Liang , Sun Im-Meng , Sun Im-Hong , Arwood Matthew , Xu Wei , Collins Samuel , Leone Robert , Prchalova Eva , Rais Rana , Slusher Barbara , Horton Maureen , Zahnow Cynthia , Powell Jonathan 
Published: August 2019

Malignant ascites in ovarian cancer develops in the setting of recurrent and advanced metastatic disease and is associated with poor prognosis. Emerging evidence has demonstrated that ovarian cancer patients have altered metabolism and an immunosuppressive environment in the ascites fluid. Inasmuch as the rapid proliferation of ovarian cancer cells and development of ascites is dependent on glutamine metabolism, we hypothesized that targeting the glutamine metabolism can inhibit the development of ascites and enhance anti-tumor immunity in ovarian cancer. To test this hypothesis, we developed a novel small molecule glutamine antagonist (prodrug of 6-Diazo-5-oxo-l-norleucine, JHU-083). By employing JHU-083, we evaluated this hypothesis in mice bearing an aggressive and metastatic ovarian cancer (ID8 cell line with an overexpression of Defb29 and Vegfa). Targeting glutamine metabolism led to markedly reduced progression of ascites along with reduced tumor cell numbers. Furthermore, JHU-083 treatment also led to a marked diminution of the volume of fluid in mice with already established ascites. Inhibition of glutamine metabolism also led to a less suppressive tumor microenvironment by blocking the recruitment of myeloid derived suppressor cells (MDSCs) and tumor-associated macrophages (TAMs) to the ascites fluid. Functionally, both the TAMs and tumor cells from the JHU-083 treated group showed a lower expression of PDL1 compared to the vehicle treated group. Additionally, we also observed reduced regulatory T cell (T regs) percentages and numbers with JHU-083 treatment. These findings are consistent with our previous observations that targeting glutamine metabolism can inhibit the generation and recruitment of MDSC and T regs by targeting both tumor cell and immune cell metabolism. Further, LC-MS based metabolite analysis of the ovarian cancer ascites fluid from JHU-083 treated mice revealed distinct differences in urea-ornithine pathway, nucleotide synthesis, and redox balance related metabolites. In light of these findings, ongoing experiments are examining the efficacy of JHU-083 in combination with epigenetic drugs, VEGF inhibitors, PARP inhibitors, and checkpoint blockade. These studies suggest that targeting glutamine metabolism may represent a novel approach to treating metastatic ovarian cancer and ascites.

Citation Format: Min-Hee Oh, Meghan Travers, Stephen Brown, Liang Zhao, Im-Meng Sun, Im-Hong Sun, Matthew Arwood, Wei Xu, Samuel Collins, Robert Leone, Eva Prchalova, Rana Rais, Barbara Slusher, Maureen Horton, Cynthia Zahnow, Jonathan Powell. Targeting glutamine metabolism as a mean of treating a murine model of ovarian cancer and ascites development [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr LB-022.