Pancreatic cancer overall has a poor five-year survival rate of less than 8%. Well-tolerated regimens and immune cell infiltration to promote anti-cancer treatments are major challenges. Studies described herein leveraged testing different combinations/doses of polyamine targeting inhibitors to further understand the impact of targeting key polyamine pathway mediators in pancreatic ductal adenocarcinoma (PDAC). Placebo controls were compared to groups treated with difluoromethylornithine (DFMO, a polyamine biosynthesis inhibitor of ornithine decarboxylase), different polyamine transport inhibitors, and compound combinations in strategies for polyamine blockage therapy (PBT). Informatic analyses showed that the dysregulation of key polyamine pathway mediators are associated with poor patient prognosis. A PBT strategy combining DFMO and Trimer44NMe was well tolerated over extended treatment in a syngeneic, immunocompetent mouse model. This in vivo PBT strategy significantly reduced tumor size and increased survival in comparison to DFMO alone. Results also showed increased infiltration of CD86+ immune cells into the PDAC tumor in DFMO and/or the PBT combination, although further investigation is needed to understand their impact on the PDAC microenvironment. A second PBT strategy that combined DFMO and a non-polyamine-based inhibitor (GW5704) was effective against PDAC cells in vitro and in immunodeficient mice, but not in the immunocompetent mouse tumor model used above. Only tumors treated with DFMO exhibited downregulation of MYC and significantly increased infiltration of T cells. Overall effectiveness of a PBT strategy was dependent on the drug that was combined with DFMO. MYC suppression was linked to improved survival and immunomodulatory changes in the pancreatic tumor microenvironment. Overall, the present study points to DFMO being an immunomodulatory agent, and a need for further understanding of DFMO-based polyamine-inhibitory therapeutic strategies in PDAC. Further studies are need to understand how PBT treatment can improve in vivo therapeutic outcomes in part through immune modulation in the tumor microenvironment.
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Doctor of Philosophy (Ph.D.)
College of Medicine
Burnett School of Biomedical Sciences
Length of Campus-only Access
Doctoral Dissertation (Open Access)
Nakkina, Sai Preethi, "Evaluating Novel Combinations of Polyamine Targeting Therapeutics in Pancreatic Ductal Adenocarcinoma" (2022). Electronic Theses and Dissertations, 2020-. 1057.