Suppression Of Clear Cell Ovarian Carcinoma Growth By Glutaminase-1 Inhibitor As Single Agent And In Combination With Parp-1 Inhibitor

Tumor hypoxia and cancer-associated mutations reprogram central carbon metabolism and enhance the dependence of cancer cells on glutamine for growth. Clear cell ovarian cancer (CCOC) is a unique epithelial ovarian cancer histotype that is less responsive to chemotherapy and has poorer prognosis than serous histotype. Whole genomic analysis identified major pathways activated in clear cell involving in hypoxic cell growth and carbohydrate metabolism, which were driven by hypoxia-inducible factors HIF1a and/or 2a. We demonstrated before that treatment of HIF-expressing cancer cells with glutaminase 1 (GLS1) inhibitor CB-839, restricts nucleotide synthesis and causes DNA replication stress, which sensitizes cells to the PARP-1 inhibitor. Herein, we observed a range of sensitivities to CB-839 treatment in vitro in CCOC cell lines, from which we selected 4 most sensitive cell lines (ES2, SMOV2, TOV21G and RMG1) and 4 most resistant cell lines (OVSAYO, KK, HAC2 and OVISE) for further study. The synergistic effect of combination treatment of CB-839 and olaparib was achieved in all eight cell lines in vitro . To identify more molecular and metabolic biomarkers of CCOC sensitivity to GLS1 inhibitors, we are currently profiling the gene expression signatures of the most sensitive and resistant CCOC cell lines by RNAseq as well as and the metabolic profile of the CCOC lines. To test the sensitivity of the ES2 cells in vivo to a GLS1 as a single agent or in combination with PARP-1 inhibitors we injected them orthotopically in nude mice. Thirty mice bearing growing ES2 derived tumors were randomly assigned into four groups: vehicle control (n=8), treatment with CB-839 (200mg/kg, gavage, twice daily, n=7), olaparib (75mg/kg, gavage, once daily, n=7) or their combination (n=8). We monitored tumor growth by serial bioluminescence imaging, animal body weight as well as animal survival. To date, after 15-day treatment, we detected a synergistic effect between the 2 agents CB-839 and olaparib in controlling ovarian tumor growth in vivo. Our work discovered a range of sensitivities of CCOC cell lines to GLS1 inhibitor and supports the therapeutic strategies of combining GLS1 inhibitor and PARP inhibitor for targeting HIF-driven CCOC. Citation Format: Tianjin Yi, Danos Christodoulou, Arimichi Okazaki, Michael Birrer, Othon Iliopoulos. Suppression of clear cell ovarian carcinoma growth by glutaminase-1 inhibitor as single agent and in combination with PARP-1 inhibitor [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr LB-253.