Abstract A88: The synthetic triterpenoid CDDO-Imidazolide reduces immune cell infiltration and cytokine secretion in the KC mouse model of pancreatic cancer

Abstract

Abstract Survival rates for pancreatic cancer remain at 7-8%, and as the incidence and deaths are expected to increase, new drugs are needed for the prevention and treatment of this devastating disease. LSL-KrasG12D/+;Pdx-1-Cre (KC) mice replicate the genetics, symptoms and histopathology found in human pancreatic cancer. Immune cells infiltrate into the pancreas of these mice and produce inflammatory cytokines that promote tumor growth. This process can be accelerated with the administration of lipopolysaccharide (LPS) or caerulein so KC mice at 9 weeks of age were injected once a week for 4 weeks with LPS (4mg/kg). One or four weeks after the LPS injections, plasma, pancreas and spleens were collected. KC mice were particularly sensitive to the effects of LPS, as only 48% of the KC mice survived an LPS challenge while 100% of wildtype (WT) mice survived. Survival was increased when KC mice were pre-treated with the triterpenoid CDDO-Imidazolide (CDDO-Im) (71% survival). LPS increased the percentage of CD45+ immune cells in the pancreas and immunosuppressive Gr1+ myeloid derived suppressor cells (MDSC) in the spleen of KC mice. In contrast, CDDO-Im decreased the infiltration of CD45+ cells into the pancreas and the percentage of Gr1+ MDSC in the spleen of KC mice challenged with LPS. Levels of inflammatory cytokine levels also were markedly higher in KC mice vs. WT mice challenged with LPS. Pre-treatment with CDDO-Im decreased the production of IL-6, CCL-2, VEGF, and G-CSF in the KC mice. These cytokines are prognostic markers in pancreatic cancer or play important roles in the progression of this disease. Disrupting inflammation during tumorigenesis with drugs such as CDDO-Im might be useful for preventing pancreatic cancer, especially in high risk populations. Citation Format: Ana Sofia Leal, Michael B. Sporn, Patricia A. Pioli, Karen T. Liby.{Authors}. The synthetic triterpenoid CDDO-Imidazolide reduces immune cell infiltration and cytokine secretion in the KC mouse model of pancreatic cancer. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2016 May 12-15; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2016;76(24 Suppl):Abstract nr A88.