Pancreatic cancer is the fourth leading cause of cancer death in the US with a 5 year survival rate of 6%, highlighting the need for new treatments. The receptor for advanced glycation end products (RAGE) has emerged as a potential chemotherapeutic target in pancreatic cancer. RAGE is expressed by pancreatic cancer cells and is associated with their increased proliferation and high metastatic potential. RAGE promotes constitutive activation of NFkB and phosphorylation and mitochondrial translocation of STAT3 leading to chronic inflammation and resistance to apoptosis. RAGE is also known to regulate autophagy in pancreatic cancers, which facilitates tumor growth. Silencing of RAGE through siRNA leads to enhanced apoptosis and decreased autophagy in pancreatic cancer cells and reduced the growth of tumors when these cells were injected into mice. Silencing of RAGE also reduces levels of autophagy markers that are basally elevated in pancreatic cancer. Soluble RAGE is a negative regulator of RAGE function and its levels inversely correlate with pancreatic cancer etiology. RAGE appears to be an important regulator of inflammatory, stress and survival pathways that contribute to resistance to chemotherapy, enhanced proliferation and the high metastatic potential of pancreatic cancer. The oceans are a rich source of bioactive natural products. The uniqueness, chemical diversity and complexity of marine natural products represent an unexploited supply of potential new drugs, lead compounds for medicinal chemistry or biological probes to allow for better understanding of diseases. Harbor Branch Oceanographic Institute (HBOI) has developed a unique screening library of secondary metabolites isolated from deep water marine invertebrates. This library will be used in the proposed research. The objective of this exploratory project is to initiate a screening effort aimed at identifying novel marine natural products that target the receptor for advanced glycation end products (RAGE). These small molecules have the potential to be useful as chemotherapies against pancreatic cancer, or useful as tools to further our understanding of the role of RAGE in this disease. The first specific aim of the proposed research is to develop and implement cell-based 96-well-format screening assays to screen materials for their ability to a) decrease levels of membrane bound RAGE in pancreatic cancer cells, and b) increase levels of soluble RAGE secreted by pancreatic cancer cells. The second specific aim is to screen 1000 materials from the HBOI library, selected to provide chemical diversity, to identify compounds with the ability to inhibit RAGE. Based upon past experience we are confident that we will find actives within this screening set. Our third specific aim is to conduct dereplication, begin isolation/structure elucidation and, if time and budget permit, secondary biological testing of the top hits in the assay.
The proposed exploratory research seeks to initiate a screening effort for inhibitors of the receptor for advanced glycation end products (RAGE) in pancreatic cancer cells using a unique library of marine natural products. RAGE has emerged as an important regulator of inflammatory, stress and survival pathways which contribute to the resistance to chemotherapy, enhanced proliferation and the high metastatic potential of pancreatic cancer.