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

Abstract

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.