Pancreatic cancer (PC) is a challenging cancer to treat, with a 5 year survival of < 13% in the United States. This is attributed to multiple histologic subtypes, extensive desmoplastic reactions, resistance to chemotherapy, profound immunosuppression and crosstalk between tumor, immune and stromal cells in the microenvironment. Alternative modalities are needed to treat this aggressive tumor. Our laboratory has shown that targeting polyamines using a polyamine blockade therapy (PBT), which is a combination of Difluoromethylornithine (polyamine synthesis inhibitor) and Trimer44NMe (polyamine transport inhibitor), is effective against PC. In the present study, we used a KPC genetic model of PC, as it mimics human tumors from spontaneous tumor conception to metastasis. Despite tumor heterogeneity, PBT improved outcomes in KPC mice. Histopathology revealed decreased tumor size, variable decrease in tumor weights, and significant stromal alterations. Stromal alterations were driven by reduced collagen deposition. PBT was found to variably inhibit markers associated with cancer-associated fibroblasts and activated pancreatic stellate cells, which are key producers of collagen. Also, M1 macrophage associated markers were upregulated in the microenvironment. To elucidate the effect of PBT on cells known to contribute to the immunosuppressive environment in PC, we treated bone marrow-derived myeloid derived suppressor cells (MDSC). We found using flow cytometry that PBT inhibited the abundance of PMN (polymorphonuclear)-MDSC phenotype. Finally, RNA sequencing revealed that PBT inhibited genes involved in chemotaxis and inflammation associated with MDSC biology. Collectively, this work provides the basis for feasibility and utility of testing PBT in larger cohorts of the KPC model.
| Identifer | oai:union.ndltd.org:ucf.edu/oai:stars.library.ucf.edu:etd2020-2824 |
| Date | 15 August 2023 |
| Creators | Gandhi, Manav |
| Publisher | STARS |
| Source Sets | University of Central Florida |
| Language | English |
| Detected Language | English |
| Type | text |
| Format | application/pdf |
| Source | Electronic Theses and Dissertations, 2020- |
Page generated in 0.0018 seconds