RAGE inhibitors and gemcitabine: an effective combination to attenuate pancreatic cancer

[Speaker] Priyanka Swami:1
[Co-author] Estelle Leclerc:1, Michael Hollingsworth:2, James Grunkemeyer:2, Prakash Radhakrishnan:2, Tom Caffrey:2, Prathamesh Patil:2, Simon Shin:2, Ayrianne Crawford:2, Kelly Connell:2
1:Pharmaceutical Sciences, North Dakota State University, USA, 2:University of Nebraska Medical Center, USA

Pancreatic cancer (PC) is currently the fourth leading cause of cancer deaths in the US. For decades, gemcitabine has been used as the standard treatment for PC. However, it offers a modest survival advantage which can be attributed to dense stroma and restricted vasculature in pancreatic tumors, as well as development of chemo-resistance. Receptor for Advanced Glycation End products (RAGE), a cell surface receptor, has been demonstrated to contribute in PC progression. RAGE interacts with several ligands and promotes pancreatic tumor cell survival by supporting autophagy and limiting apoptosis. Recent reports have illustrated that gemcitabine treatment results in the release of HMGB1 from necrotic cells. HMGB1, an important ligand for RAGE, leads to RAGE upregulation in tumor, making it chemo-resistant. We intend to utilize a combination of RAGE inhibitors and gemcitabine to target pancreatic cancer. We propose that RAGE inhibitors can prevent the RAGE-ligand interaction, thereby sensitizing PC for gemcitabine.
To accomplish the aim of our study we employed orthotopic mouse model of PC. KPC cells, derived from mice tumors, were implanted in the pancreas of C57BL/6 mice. The mice were divided into four treatment groups: (i) Saline control (ii) Gemcitabine (iii) RAGE inhibitor (anti-RAGE antibody, IgG2A11) (iv) RAGE inhibitor + gemcitabine. At the end of the study, the tumors obtained from the different treatment groups were assessed for their size, weight and volume. Additionally, the tumors from the four treatment groups were analyzed for the expression of markers of cell proliferation (Ki67), autophagy (LC3), apoptosis (cleaved caspase 3) and cell survival (BCl2) by western blot and immunohistochemistry. We also compared the phosphorylation of ERK1/2 in the tumors from the four treatment groups by western blot.
The data showed a statistically significant reduction in tumor weight in mice treated with the combination of anti-RAGE antibody, IgG2A11 and gemcitabine as compared to the control group. We could also observe a significant decrease in the expression of LC3 and an increase in cleaved caspase 3 in the tumors treated with the combination. There was also a significant reduction in the phosphorylation of ERK1/2 in tumors treated with anti-RAGE antibody IgG2A11 and gemcitabine.

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