Abstract 4047: Pegcrisantaspase-based combination therapies for the treatment of pancreatic adenocarcinoma

Abstract

Abstract Pancreatic adenocarcinoma is one of the most aggressive human cancer types and is predicted to be the second leading cause of cancer-related deaths in the United States by 2030. Currently, there is no FDA- approved chemotherapeutic, targeted, or immunotherapy regimen that provides meaningful clinical outcome for metastatic pancreatic cancer after failure of the first-line and second-line therapies including anti-metabolites, platinums, and topoisomerase inhibitors. Thus, there is an urgent need for novel therapeutic strategies. Pancreatic cancer cells are dependent on glutamine for tumor growth and are sensitive to glutamine deprivation. L-asparaginase is an enzyme that hydrolyzes asparagine and glutamine to aspartate and glutamate, respectively, and has been proven to deplete glutamine in the plasma in vivo. Interference with glutaminolysis or decrease in plasma glutamine concentration has been shown to activate mitochondrial apoptotic pathways, suggesting that asparaginase therapy would synergize well with other inducers of mitochondrial regulated apoptosis. Bcl-2 is a major anti-apoptotic protein and dysregulated Bcl-2 expression correlates with apoptotic resistance and metastatic potential of pancreatic carcinoma. We hypothesized that in pancreatic adenocarcinoma, glutamine depletion induced by pegcrisantaspase (PegC), a longer-acting pegylated asparaginase derived from Erwinia chrysanthemi, will synergize with the FDA-approved Bcl-2 inhibitor venetoclax (Ven). Using human pancreatic adenocarcinoma cell lines, we found that PegC has potent anti-cancer activity in vitro. The IC50 of PegC in MIA PaCa-2, SW 1990, and BxPC-3 was determined to be 0.08, 0.01, and 0.013 IU/mL, respectively. Ven demonstrated in vitro anti-cancer activity only in BxPC-3 cells (IC50 11.1 µM), perhaps related to the absence of K-Ras mutation in this cell line. We tested the efficacy of Ven-PegC combination therapy in vivo using a xenograft flank tumor model with MIA PaCa-2 cells in NRG mice. Tumor-bearing mice were treated with Vehicle, Ven, PegC, or Ven-PegC combination and tumor volume was monitored. Tumors were excised and weighed at the conclusion of the study. Ven-PegC combination therapy was the only treatment to significantly (p<0.05) reduce tumor burden, with an average tumor weight of 0.38g versus 0.89g and tumor volume of 1074.8 mm3 versus 2013.5 mm3 in Ven-PegC vs control-treated mice. Ven-PegC treatment also significantly reduced plasma glutamine levels compared to levels in vehicle-treated mice (619.3µM in control vs 11 µM in Ven-PegC, p=0.0001). Ongoing work is focused on delineating the anti-cancer mechanism of Ven-PegC therapy, testing the combination of PegC with current standard-of-care anti-pancreatic cancer chemotherapeutics, and investigating the efficacy of single-agent PegC in metastatic pancreatic adenocarcinoma. Citation Format: Dominique Bollino, Sophie Nerone, Xinrong Ma, Kayla M. Tighe, Brandon Carter-Cooper, Rena G. Lapidus, Ashkan Emadi. Pegcrisantaspase-based combination therapies for the treatment of pancreatic adenocarcinoma [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 4047.