Abstract 3546: DFMO based improvement in survival of pancreatic cancer-bearing mice is associated with modulation of immune suppression in the tumor microenvironment

Abstract

Abstract Existing therapeutics have failed to improve pancreatic ductal adenocarcinoma (PDAC) patient outcomes, in part due to tumor associated immune suppression and upregulation of compensatory mechanisms. KRAS and c-MYC are important oncogenes in PDAC linked to tumor immune suppression. We describe the use of difluoromethylornithine (DFMO) and a c-RAF inhibitor (GW5074) to indirectly target c-MYC and KRAS, respectively. DFMO in combination with GW5074 was tested for ability to improve pancreatic cancer outcomes. Pancreatic cancer cells showed decreased cell viability and increased apoptosis in response to a combination of DFMO + GW5074. In vivo orthotopic models of pancreatic tumors had decreased tumor weight in DFMO + GW5074 treated mice, when compared to control group. However, only treatment with single agent DFMO resulted in improved survival of immunocompetent pancreatic tumor bearing mice with respect to control, in contrast to treatment with GW5074 alone or DFMO + GW5074. To understand why the in vivo data was contrary to in vitro results, immunohistochemical analysis of immune cells in the tumor microenvironment was used to reveal increased expression of markers associated with anti-tumor effects such as CD86, CD3, CD4 and CD8 in DFMO treated tumors. Tumors treated with DFMO also displayed decreased expression of MYC, suggesting that DFMO-associated MYC suppression could be linked to decreased immune suppression in the tumor microenvironment and improved survival. In contrast, GW5074 treatment maintained MYC expression in tumors. Overall, the present study points to DFMO being an immunomodulatory agent, and a need for further understanding of DFMO-based therapeutic strategies in PDAC. Citation Format: Sai Preethi Nakkina, Sarah B. Gitto, Jordan M. Beardsley, Veethika Pandey, Michael M. Rohr, Jignesh Parikh, Otto Phanstiel, Deborah A. Altomare. DFMO based improvement in survival of pancreatic cancer-bearing mice is associated with modulation of immune suppression in the tumor microenvironment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3546.