The University of Florida Health Cancer Center has awarded a 2019 GI, Lung & Prostate Cancer Research Pilot Project to Dr. Maria Zajac-Kaye, Department of Anatomy and Cell Biology and Dr. Timothy Garrett, Department of Pathology, Immunology, and Laboratory Medicine
Title: Targeting nucleotide synthesis and defining metabolic pathways in Kras– driven pancreatic cancer
Pancreatic cancer remains a lethal, RAS-driven cancer with an incidence that has increased 60% over the past decade. Current chemotherapeutic regimens fail to meaningfully extend survival and result in drug resistance. RAS is a key initiator in development of pancreatic cancer, however, sequential somatic aberrations are required for progression into advanced metastatic disease. Our lab showed that overexpression of Thymidylate Synthase (TS), an essential DNA synthesis and repair enzyme, plays a direct role in promoting pancreatic tumorigenesis. To determine whether TS enhances the neoplastic effects of oncogenic KRAS, we established a novel genetically engineered mouse model (GEMM) for pancreatic ductal adenocarcinoma (PDAC) by generating conditional KrasG12D mutant mice that express high levels of human TS (hTS) in the pancreas. We found that overexpression of hTS accelerates tumor development of hTS/KrasG12D mice. TS also plays a key role in folate metabolism, known to contribute to nucleotide pool replenishment during cell proliferation. Together with the methionine cycle, the folate cycle is part of the 1- carbon (1C) metabolism. These two cycles integrate cell nutrient status using 1C groups from glycine and serine to generate nucleotides, glutathione and other metabolites that are required for DNA and RNA biosynthesis. In the last decade, it has become apparent that alterations in cellular metabolism are a hallmark of cancer cells and that a rewired metabolism is essential for rapid tumor growth and proliferation. Pharmacological inhibition of 1C metabolism with antifolates and nucleoside analogs such as the widely-used first-line chemotherapeutics gemcitabine and 5FU has been used as anticancer therapy for many years. However, cells become resistant to treatment by overexpressing TS. This suggests that metabolic pathways are important mediators of resistance toward anticancer agents. Thus, the main goals of the current proposal are first, to analyze in Aim 1 the global metabolome, lipidome and 1C pathway profile in mutant Kras-derived tumors overexpressing hTS to understand the mechanism by which TS accelerates mutant Kras driven PDAC progression. Second, we will inhibit TS in our hTS/KrasG12D GEMM using TS inhibitors alone or in combination with KRAS pathway inhibitors in Aim 2. We have proven in pancreatic tumor cell lines that TS and mTOR inhibition exerts a synergistic anti-tumoral effect and do not promote drug resistance. Finally, in Aim 2, we will analyze the metabolome, lipidome and 1C pathway of hTS/KrasG12D treated tumors to identify metabolic pathways that are associated with the antitumoral effect of the TS inhibitors as potential candidates for pharmacological intervention. A better understanding of the altered metabolism in PDAC will provide insights into the molecular mechanisms of the disease and will identify novel metabolic targets that could be used for combinatorial therapy with TS inhibitors that may increase the life span of PDAC patients and potentially offer long-term treatment options.