Abstract PO-120: Differential expression of polyamine pathways in human pancreatic tumor progression and effects of polyamine blockade therapy on the <i>in vivo</i> pancreatic tumor microenvironment
Authors: Sai Preethi Nakkina, Sarah B. Gitto, Veethika Pandey, Jignesh G. Parikh, Dirk Geerts, Kenneth P. Olive, Otto Phanstiel, Deborah A. Altomare, Carlo Maurer
Journal: Cancer Research (2021)

Abstract Pancreatic cancer is the fourth leading cause of cancer death in the United States, with a five-year survival rate of less than 8%. Existing therapies have failed to improve pancreatic ductal adenocarcinoma (PDAC) patient prognosis. The dense desmoplastic reaction which occurs in PDAC makes it challenging for drugs and immune cells to infiltrate the fibrotic barrier. There is a need to exploit lesser explored targets in PDAC that can influence both the tumor and its microenvironment. One such avenue could be via targeting polyamine metabolism which is upregulated in pancreatic tumors. Though aberrant polyamine upregulation in pancreatic tumors has been known for decades, there has been little progress in translating this information into a PDAC therapeutic strategy. Additionally, there is a dearth of information regarding the dysregulation of polyamine metabolism in human PDAC and its association with clinical outcomes. Thus far, preclinical studies targeting polyamines using polyamine blockade therapy (PBT) has improved survival of pancreatic tumor bearing mice. Literature shows effectiveness of PBT in eliciting an anti-tumor immune response in other tumor types. Whether these results translate to the immune-privileged PDAC microenvironment need to be determined. The present study explores polyamine gene expression in human PDAC samples by mRNA expression analysis of frozen PDAC and Pancreatic intraepithelial neoplasia (PanIN). The Cancer Genome Atlas in the public domain was used to identify clinical outcomes of PDAC patients associated with select polyamine gene expression. Further, the anti-tumor effects of PBT and associated tumor microenvironment changes were identified using in vivo PDAC models and histological assessment. Polyamine dysregulation was found to be evident in human PDAC progression. Also, increased expression of certain polyamine-related genes was associated with poorer survival of pancreatic cancer patients. When targeting polyamines using PBT in immunocompetent C57Bl/6 mice with Pan02 tumor cells injected in the pancreas, PBT significantly increased overall survival. PBT also resulted in an increase in the infiltration of macrophages (F4/80) and expression of T-cell co-stimulatory marker (CD86) as assessed by immunohistochemistry and further quantification of imaging. Based on these changes, we hypothesized that PBT could prime the tumor microenvironment to be more susceptible to existing therapeutics. In conclusion, targeting polyamines using PBT results in increased survival and immune modulation in PDAC. Citation Format: Sai Preethi Nakkina, Sarah B. Gitto, Veethika Pandey, Jignesh G. Parikh, Dirk Geerts, Kenneth P. Olive, Otto Phanstiel, Deborah A. Altomare, Carlo Maurer. Differential expression of polyamine pathways in human pancreatic tumor progression and effects of polyamine blockade therapy on the in vivo pancreatic tumor microenvironment [abstract]. In: Proceedings of the AACR Virtual Special Conference on Pancreatic Cancer; 2021 Sep 29-30. Philadelphia (PA): AACR; Cancer Res 2021;81(22 Suppl):Abstract nr PO-120.